Alzheimer's disease (AD) is a genetically complex disorder that accounts for the majority of dementia in the elderly population. Over 100 rare, highly penetrant mutations have been described in three genes ( APP, PSEN1, PSEN2) for early-onset familial AD. In the more common late-onset form, a polymorphism in the apolipoprotein E gene has been associated with increased susceptibility. However, recent studies suggest that these four genes account for less than 30% of the genetic variance for AD and that more genetic factors remain to be identified. In this review, we present a brief history of AD genetics and preview some of the next frontiers in Alzheimer gene discovery primarily focusing on chromosomes 12, 10, and 9.