Obsidian Entertainment approached Bethesda after the release of Fallout 3 stating they were interested in developing a Fallout spin-off. Bethesda agreed to allow it, and stated they should place their game in western America to differentiate their game from Fallout 3 which took place in eastern America. Luckily Obsidian was already thinking of using Vegas as the game's location, and Bethesda loved that.
When taking the NCR citizenship test, one of the questions asks who the first NCR president was, with the correct answer being Tandi. Tandi was actually an NPC the player character saved in Fallout 1, before the NCR was formed and when she was just a resident of the small town known as Shady Sands.
If you choose the Wild Wasteland perk at the start of the game, you can find an old fridge in the desert with a fedora-wearing skeleton inside. This is a reference to Indiana Jones and the Kingdom of the Crystal Skull, in which Jones takes shelter in a fridge to avoid a nuclear blast
In the 2010 expansion "Dead Money", Courier 6 sets off to locate the signal of an invitation for the grand opening of the Sierra Madre Hotel. The expansion was inspired by the novel and 1948 film adaption starring Humphrey Bogart "The Treasure of the Sierra Madre". In the film and book, a group of compatriots set off to find the lost treasure of the Sierra Madre.
The town of Novac gets its name from the sign outside the motel beside the large T-Rex. The sign reads "NO VACANCY" with the letters "ANCY" destroyed and burnt out, leaving just "NOVAC" illuminated.