Origins, Columbus, in late June http://www.originsgamefair.com/
Gencon, Indianapolis, early August http://www.gencon.com/2010/indy/default.aspx
Dragoncon, Atlanta, early September http://dragoncon.org/
Origins is mostly gaming: board, card, RPG, LARP, and seminars on gaming and military studies.
Gencon is mostly RPG, with some other types of gaming and seminars.
Dragoncon is a mix of gaming (all styles) and seminars about literary, television, and cinema SF and fantasy.
Go if you are close and have the bucks! Very fun!