Something that has often captured my imagination is places that have, for one reason or another, only been visited by few mortals. It could be that it’s sacred to divinity and blocked off from anyone without special dispensation, so thoroughly tainted by evil that death is the best most people entering it can hope for, full of primordial beasts that don’t fear any weapon humanity can bear against them, has local physics that don’t support our existence, or are simply to distant and hard to find. Some examples include Ash Lake from Darksouls, Red Mountain from Morrowind, and the Black City from Dragon Age.

So I wanted to hear about any locations from your campaign settings for which, when the party visits there, they’re officially walking into unknown territory.

In mine, it’s the Amber City. Deep below the surface, beyond even the homes of drow and drugar, so far that you couldn’t even tell if you’re still on the same plane, it lies in an expanse of pure black. Amber light radiates off its buildings and streets, the only source of illumination against a “sky” that cannot be seen. While the empires that rise and fall will claim either Elucinor or Vanalesse as their capital, the Amber City is where the plane of Resphar is really run, the seat of the Secret Rulers that the spirits over these cities swear fealty too.

The city is massive, it’s population needing no food and thus no agricultural settlements to support it. Inside are the spirits that serve the Secret Rulers’ plans, sorrowsworn crafted from the failures and regrets of their enemies, hags and eyes of fear and flame that play on the weaknesses of kings and peasants alike, unspeakable horrors that crush inconvenient populations, and even some celestials deceived by their pride. There are also star spawn, though they don’t serve the Secret Rulers, instead being allowed to watch over their master, the Masolat, who is imprisoned in one of the city wards.

The surest way in is through the roots of Yulathe, the first being born of Resphar that has since been corrupted into a Gulthias tree. Those few that do manage to make the trip into the city without authorization are captured, turned into undead, and trapped within the prison district.

In my longtime homebrew project of Avem, the world's a single landmass separated by three great rivers, creating three continents. At the center of the continents, where the rivers connect, is the Sea of Waterfalls. Created by a divine blast of energy which carved a gigantic hole into the earth, it's surrounded by sheer walls that delve hundreds of feet below sea level (outer sea level, that is). Completely impassable, no climbing down them. For a long time, it was impossible for people just to reach the bottom of the sea, until certain means were invented for scaling the three waterfalls that feed into it (airships, boats with mechanical spider legs, and a giant elevator built for ships). 

If you manage to breach the Sea of Waterfalls (and avoid the lightning-powered demigod turtle that swims through it), you'll find at the center of this sea is the Island of Zenshar, which was the homeland of dragons before they went extinct. This island is claimed by various nations who seek to harvest the ichor (dragon fossil fuel, essentially) which is found so richly on the island, more so than anywhere else in Avem. Not only must adventurers deal with the political tensions of these countries and their soldiers, but also the strange, haunting feeling of dragons watching them from the grave. Perhaps not all the dragons are extinct...

Few dare to tread the roads of the Underworld, but that's more an informed attribute because they're meant to be a fast travel system. In ages past a race--and I really should say species because their biology uses inversely chiral proteins to our own making our food poison to them--of giants made paths through the earth to various destinations of interest in the conworld. When refugees from future Earth arrived, a bitter war forced the giants into hiding in these tunnels. Later, they chose undeath as a way to exact eternal vengeance. There are few encounters on the Underworld paths, but what encounters there are consist of cyclopean monstrosities that use the attribute scores of giants, the spell casting and legendary actions of Mummy Lords, with the undead fortitude of zombies. However, the places these roads lead to are truly hidden.

Two paths lead between the cities of the south and the northern archipelago. These are causeways for PCs and NPCs to move and shake the world. Maybe it's only the hill giant's stats I'll use when an encounter is appropriate. Phase spiders and goblins may even be called for. But other paths exist. One leads south to the pole of the world and the city called by its inhabitants "Heaven." In that city is an artifact I've called a Prognostication Engine. If you choose to follow that path, be prepared to face armies of Celestials who know you're coming and in what number and with what powers and abilities (also what creatures types for the purposes of the Solar's arrows). Another path leads east to the Broken Shore. In ages past an empire of man united the southern city states, holding court at the fortress in Uloomu. These forebearers were opposed by a group which the few surviving records call the Enemy from Across the Waves. In an effort to oppose this mysterious foe, an expeditionary force was sent to found Fort Ghul on that far promontory. While the cities of the south fell into provincialism with the passing of years, Ft. Ghul preserved the flower of Chivalry from that ancient strength. If they were to discover that the Old Empire has not endured, they would have no choice but to mount a crusade to reinstate Imperial rule. Pity the PCs who accidentally rouse the army of 10th level battlemasters with half-fey ancestry and their leadership of 20th level sword and glamour bards. Yet another path leads northwest. The exedus from future Earth was not an orderly affair. One group who landed on a continent north of the one I've fleshed out for adventuring began reconstructing their society of the future--complete with arcologies and transdimensional communication. One of the first things they sought to do was to contact Earth. That didn't work out. Instead, they shifted every living being in the city's environs into the ethereal creating a necropolis where PCs will struggle to discern what is a hologram and what is a specter, wraith, or ghost. In the time since, Tabaxi have reclaimed the concrete jungle--perhaps even expanding their society to become the Enemy from Across the Waves (haven't quite worked that bit out yet).

Two other farthest shores await players who have the patience to see all ages of the world. The Ethereal Plane, The Feywild, The Shadowfell, The Elemental Planes and a few others are all cardinal directions within the world's reflection. Gate and Planeshift don't quite work as written in this cosmology (but are no less powerful). Beware sojourning in the Otherworld. You may meet the literal incarnation of your character's mortality--which could decide to take a liking to your character! Also, there's a silver dragon that lives on the moon, and while the only portal I know of to get there has been repurposed, that doesn't mean a dedicated PC couldn't recover it. And by dedicated I mean Earth's enemies didn't die with future Earth. Pity the PCs who have progressed to the point where the only way I can challenge them is with (PC lvl +1) superhumans from the beyond the stars!

Then... There's one final surprise. The slowest assassin... Players who have visited this world more than once will eventually become familiar with the city called "Heaven," just as they will become familiar with the land of Faerie being at the center of every forest, and the Demonic Parliament being located underneath a volcano. The inhabitants of that city are living on borrowed time. A plague of lycanthrope will annihilate them long before PCs end their days in this world. However, the secret they will take with them is that in order to construct the city, they needed to make safe the world from a primordial leviathan. The World Serpent is buried beneath the ice on which Heaven rests. Pity the PCs who believe the world holds no more surprises for them.

There are the dream planes. Few have traveled there, other than by the normal nightly means, which isn't travel so much as an alter ego that resides there and sleeps when you're awake and wakes when you're asleep.

There is also the watery abyss, where fearsome aberrations dwell. And there is the celestial plane above heights that can only be reached by magical flight or immense towers at the corners of the world.

But that's mostly my planar cosmology.

There's also the Sand Sea, an immense and hostile desert that few have ever crossed. And lately the seas have been wild, and only a suicidal sailor would venture out of sight of the shore.

There are also mountain peaks so high that even aarakocra can't fly over them, and the cold and avalanches pose a deadly danger.

The corners of the world where the Pillars of the Sky stand are uninhabited and uncharted, although not unreachable by intrepid adventurers.

There is a library in the middle of a desert. Perfectly preserved by a genie of some kind. Nobody has ever been able to enter, because the genie will only let people enter if they have proper authorization, and nobody knows what he means by that.

If the players somehow figure it out, then inside the library they will find the following:

-Modern day computers and technical books, as from a real-life university.

-A very strange treatise describing a theory about "simulating realities", and esoteric notes about using something called called "quantum physics" to "make it real"

-A copy of the D&D 5e Monster Manual, Player's Handbook, and Dungeon Master's Guide

It's at this point that you explain that the genie looks a bit unusual: It's really an AI hologram.

I have a few such places in my Homebrew world Illvicta, which I've been developing for quite a while now. I'm going to leave out the super obvious one (homeworld of the gods/elder gods etc.) and focus up on two.

The forty-eighth realm is a plane of existence located directly above hte throne of the elder gods, nobody has ever been inside of it; those that do know of it believe its where the Precursors existed before they left. 

Secondly, I have the Valley of Knowledge, this is a large gorge/valley in between a ring of forested mountains in the middle of the nation of Plu. This Valley is guarded by an Angel of Knowledge called Xavo the Seer, who's sole purpose is to keep mortals from entering the Valley. The Valley's purpose is to be a repository for old knowledge, and it is said to be filled with countless books, scrolls, tablets, and other writings that hold knowledge equal to if not beyond the combined libraries of Azgoroth, the elder god of time, and his brother Evezyke, the elder god of the forgotten. In reality, the valley holds very little knowledge compared to either one of the libraries on its own, but does hold some secrets which should be kept from mortals. 

Here's a few from my current campaign: Fate of the South Holds   

Enchanted Forest (ShadesWood): Spanning the continent coast to coast,  the Enchanted Forest (also known as ShadesWood) is an absolute unknown. It is older than recorded memory. It is even older than the memory of the Elves. It is said to be what’s left of the chaos of creation when the gods were done with their tasks. There are just a few known openings, or paths, along the northern border with The Wastes and only three on the south side... None who have made it through the forest can recall the path or accurately guide others through. Most elves fear it and avoid it if possible. Some adventurers claim to have crossed through, north to south, in as little as three days while others were lost for many months before finding a way out.

All who have made it through say the same thing: “Do not stray from the path no matter where it leads or madness will claim you.” Day and night seem to not matter in ShadesWood, as a perpetual twilight holds sway, and sounds are hard to trace. Lights and unusual sounds can be seen and heard near the edges. There are tales of all manner of unusual beasts and creatures living, and not living, within the woods. Adventurers who have made it through can sometimes, when drunk, be heard to mutter: “Beware the squirrels! The black squirrels!” but requests for more information usually lead to either a beating or defeated whimpering from the drunken adventurer.

The Wastes (Plain of the Dead): While not quite a dessert The Wastes (or Plain of the Dead) is far worse. Legends date it back to the same battle that raged across the continent in time lost. It is a vast expanse of flatlands and gullies where little grows and everything that lives is tough and mean. Days can be hot and windless while nights can be cold and eerily still. Water is usually undrinkable and hunting useless. Those who dare the crossing are of two types; those who plan carefully and are rarely ever seen again and those who don’t plan carefully and are never seen again.

Supposedly the plain is the site of an ancient battle between Dragonkind and, what was then called, Magekind. When the battle was over nothing was left alive on the entire plain and the ground smoldered for days. That battle, known as “The Killing”, marked the end of the glory of both Magekind and Dragonkind. Since those days none of the Magekind have been seen and the dragons that remain will fly over the plain but never set foot on it.

Those surviving the crossing tell tales of dragon bones strewn about and burned areas still warm after ages have past. It is said a mist rises each night that smells faintly of ash and lies thick upon the ground to the height of a Halfling. Fire is said to drive it back, and that is a good thing because, it is whispered, the once living prowl the Plain at night. The safest crossing is the longest path (south by south-east) as it means sticking to the foot of the High Spire Mountains (also called the Dragon’s Teeth) which ring the plain to the North, East, and West. It is to be noted that the “safe” route has been reported to have the charred remains of some using that path. It seems the dragons are more active nearer to The Teeth...

The High Spires (Dragon’s Teeth): Forming an elongated, roughly semi-circular, barrier around The Wastes, the High Spires, or Dragon’s Teeth, mountains are a formidable chain of peaks and cliffs higher than any others on the continent. Ancient lore holds that they were erected as a barrier to protect the ancient Magekind homeland but no one can say for sure. So high are the Spires that they shelter the southern portion of the continent and alter the weather to both north and south and the highest peaks stand above the clouds themselves. There are only a few known passes that cross them north to south and, since all lead to the Wastes, they are seldom used. Dragons of many kinds and sizes still make their homes in the mountains and can be seen circling the heights on occasion. Legends say that the high places of the Teeth hold ancient caves where hoards of treasure from ages past await discovery, though the prospect of dragon guardians ensures most remain undiscovered...