|Akiba HDR Flickr / pictureTYO|
One of the most famous of the games, Stein's Gate, also became an anime. Originally released for the Xbox it has even been ported to the PSP and is slated for a North American release in both forms. It is a time travel story and it features Akihabara against a background of intrigue, murder, and mystery. The game has an awesome opening song and animation shown below.
The Stein's Gate time travel story is partially set in the old Radio Kaikan building that has been or will be demolished (so it now belongs to the land of myth). The Radio Kaikan building was a bit of an anime store mecca and was pretty neat to walk through. It was hot and muggy the day I visited, but it was a neat little warren of stores and I love the central staircase. There are documentaries about the building and its closing along with its brief reopening for the satellite crashing event.
Another game that received a bunch of press was Akiba's Trip for the PSP which was a vampire hunting game set in Akihabara. Some weird game mechanics happen in this game such as the methods for exposing vampires to sunlight, but it has a following and you get to wander around electric town.
There are also some anime series such as Cyberteam in Akihabara, Ore No Imouto that featured the area in episode 2, Lucky Star in episode 16, and numerous manga that are set in this area. The items here are just the tip of the old iceberg and I'm sure there are tons more that also set here. Sometimes the area is used almost as an inside joke or self-parody, but it is all in fun.