Nuketown is a settlement located atop the ruins of Trottingham, and is famed for it's acceptance of Ghouls, Super Mutants, and others who can live safely with Humans and Ponies. The settlement has no connection to any factions until the Minutemares are reformed by Connor, also known as the Sole Survivor.

The city is more heavily irradiated as one gets closer to the Two-Time Crater, which is the detonation zone for both of the nuclear weapons to strike the city of Trottingham years ago.

The city's history of being hit by two nuclear detonations has become somewhat of a selling point, and is considered a place of exodus and worship for Children of Atom. The first detonation occurred during the Dimensional War when Exodus planted a nuclear device on a Midnight transport bound for the city, with the explosion killing over 5,000 unsuspecting civilians and soldiers as well as Captain Janelle of the Paladin ranks. The second detonation occurred during the Last Lights, when the Midnight launched a nuclear missile at the ruins that were being used as a Solar Accord missile base.

Two-Time Crater is so radioactive that even Ghouls find it uncomfortable to stand in. However, the irradiated water is heavily utilised by the Children of Atom living below the city in the abandoned Solar Accord base, known as the Sanctum. While the Children of Atom living there are generally accepted by those living above, many have made the Children the "bogeyman" of the town and often worry about their actions. Some even believe the Children are trying to detonate or launch the nuclear missile beneath the city in an attempt to "Divide" everyone who does not believe. The Children themselves are split on their goals, as some want to launch the missile while others wish to remain isolation.

The irradiated water is also helpful for growing "RadRoot." This plant, resembling an onion, is highly radioactive and only grows in areas of intense radiation, but when scrubbed of radiation the plant has a unique taste and texture that is sought after by the rich and the wanderers. This plant is grown within Two-Time Crater by Ghouls wearing Radiation Suits.

The town's history is a disturbed one. The ruins were first founded by Ghouls cast out from Bolt City, who named it "The Glow" due to it's massive radioactivity. The intense radiation acted as a shield, but as the radiation died down and means of scrubbing it from an area were made more available to the townspeople, the town began trading the unique RadRoot to other towns (including Bolt City as a sign of mockery). A small sect of the Children of Atom came to the city and requested a home beneath it in the unused tunnels, but were refused by the town's government. Civil unrest broke out as some Ghouls suggested the town should be open to all who wanted to live there and would do so peacefully, and eventually the town's mayor was assassinated and found cut in half at the waist with his face bashed in, most likely the result of multiple high-force impact with a blunt weapon the size of a fist. Though it isn't outright stated, there is much implication that the assassin was none other than Fielde due to his choice of weapon (a Katana and Barval Knuckles) and the fact that he is both familiar with the town and the townspeople are familiar with him. Eventually, "The Glow" became an all-life settlement and was renamed "Nuketown" due to the history of the area.

Nuketown has a famous bar known as "Blast Radius" located on the edge of the crater. This bar is popular for selling "Warwick's Willblend" and "Black Death" drinks, and the bar-tender himself (a Glowing One named Warwick) is known by most who travel through Nuketown. As such, he is familiar with nearly every faction in the Wasteland and is very well-informed when it comes to rumours and bounties. Clarence Becker chooses this bar to become a drunken wreck after the NCR was thrown into disarray after the Everfree Conflict.

Union resolves the issues with the Children of Atom beneath the city by persuading them not to launch or detonate the missile they call "The Lamb." However, all of Union's work is undone by Kate as she persuades the Children to let her launch the nuke at Mount Canter in an attempt to free Twilight Sparkle. This action causes what's left of Canterlot to fall off of the mountain, and Kate's choice reverberates through the Wasteland with some referring to her as a wildcard and in extreme cases, a psychopath. However, Kate was aware that the only ones to die in the blast would be rogue NCR forces or scavengers, both of which she considered expendable as the NCR had a new base in Manehattan. Kate's companions, who at the time were LittlePip, ED-E and Locke, had negative, neutral and positive responses to her actions respectively.

Nuketown continued to thrive years after the events of the Fallout storylines, with the launch slightly damaging the city's reputation but the destruction of the New Lunar Order and the reformation of the Minutemares encouraging many to freely travel, especially to the famous town.