So, with the likes of Minecraft and Half-Life, mods can drastically alter the game - to the point of almost creating an entirely new game using the existing assets of the original. Cry of Fear for Half-Life and The Technic Pack for Minecraft are great examples of this. But, how is modding in New Vegas? I plan on getting a gaming PC soon, so is it worth replaying on the PC with mods (I've already beat it twice, and played through all the DLC just recently also, on the Xbox 360)? Are there any truly phenomenal mods which really alter the game or add a drastic amount of content? In other words, are there any actual gameplay mods - rather than just player skins, texture packs or minor things like a new gun?

Yes there are. For example there's http://fallout.gamepedia.com/JSawyer, made by the game's lead designer which rebalances the game while making it a good bit more challenging without having to turn the ingame difficulty up. And http://newvegas.nexusmods.com/mods/40040//? adds a whole bunch of stuff like night vision, sprinting, a grenade hotkey, bullet time, etc. There are also mods that change the weather, or add a bunch of new quests, or a new companion.

There's also a total conversion in the works that is supposed to be releasing soon: http://www.moddb.com/mods/fallout-3-project-brazil

Pretty much in Fo3 morrowind oblivion skyrim FoNV anything you can dream up can be done hell you can get cars in NV and skyrim atm I'm in a underground network that seems to have many hours of exploration from A World of Pain mod. that mod adds over 110 new locations. Not to mention the plethora of weapons and armor you can get, atm my cowboy/badass/sniper runs around the waste with a cigarette in his mouth and spurs on his boots. Anything is possible in bethesda games as of late if you can dream it then most likely you can make it.