Although in areas like Appalachia, ghouls were quickly sought out and exterminated, no matter what relation they may have had with others before they became Ghouls. Within a year, the first ghouls began to appear and with them, the first fledgling settlements, like Underworld in Washington, D.C., which existed as late as 2277. People who took shelter in areas affected by it experienced radiation poisoning those who did not die became ghouls. The densely urbanized East had a great concentration of American population and was strongly affected by the nuclear fallout. The Slog, one of the most prosperous farms in the Commonwealth and ran entirely by ghouls. As they never appear outside the Divide, due to the necessity of staying near radiation sources to remain alive, the marked men became a legend in the wasteland, like the Sierra Madre, the Burned Man, or the Big Empty. The Divide flayed them alive, causing them to become dead men walking – marked for death, sustained only by the intense radiation that permeates the area. In 2277, in the Divide, nuclear warheads triggered by the Courier's delivery of an automated nuclear launch device exploded and triggered rapid ghoulification of the Legion and NCR forces engaged in battle there. To Caesar, ghouls and other mutants are irrelevant to his plans to push westward. In contrast, Caesar's Legion does not allow ghouls (along with other mutants) within their ranks, but do allow ghouls to live in their territory, such as Raul Tejada who traveled from Two Sun to the Mojave. There are also several ghoul rangers occupying Ranger Station Echo, implying some level of acceptance of ghouls serving in the NCR. The only known community of ghouls in the region is the Bright Brotherhood, a religious faction located in the REPCONN test site, founded and led by an intelligent glowing one named Jason Bright, who wants to leave Earth and go into space to find a 'new world,' a promised land foretold by Bright himself. There are usually a few ghouls living among humans in various communities performing jobs in order to survive, such as the guard Beatrix Russell and the comedian Hadrian, both of which are in Freeside. In the Mojave Wasteland, they can be found in small amounts throughout the region, but no town is completely dedicated to them. Sometime in 2242 marked the end for both Broken Hills and Gecko as they relied on the selling of and using of uranium that was mined. Though problems with equality continue, ghouls are increasingly seen as equal members of society, though their numbers steadily dwindle. This has led to a great migration and the eventual founding of a number of ghoul and ghoul-friendly settlements, including Broken Hills in 2185, the NCR state of Dayglow around 2189, and Gecko in 2235. It would finally be destroyed and most of its population killed in a retaliatory expedition by the super mutants, sent to the city after the Vault Dweller raided the Vault and recovered the water chip, eliminating the super mutant garrison in the process. The recovery operation failed, but Unity established a stronghold in the town to ensure Set's cooperation and watch for humans. After many ghouls were killed in the assault, Set negotiated peace with the super mutants, after explaining that the ghouls are indeed the vault dwellers.

The city would eventually decline, starting with the attack by Unity in 2157, who expected to find an unopened Vault in the ruins of the city.

Less than a year later, in 2084 Set wrestled control of the settlement from the original overseer and instituted his own reign, characterized by delusions of grandeur. In California, ghouls were the first group of survivors to begin rebuilding civilization – the inhabitants of Vault 12 beneath Bakersfield founded the Necropolis in the summer of 2083. Necropolis, the single largest ghoul city in New California until 2162.

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