Alzheimer's disease (AD) is highly heritable, but genetically complex. Recently, three large-scale genome-wide association studies have made substantial breakthroughs in disentangling the genetic architecture of the disease. These studies combined include data from over 43 000 independent individuals and provide compelling evidence that variants in four novel susceptibility genes (CLU, PICALM, CR1, BIN1) are associated with disease risk. These findings are tremendously exciting, not only in providing new avenues for exploration, but also highlighting the potential for further gene discovery when larger samples are analysed. Here we discuss progress to date in identifying risk genes for dementia, ways forward and how current findings are refining previous ideas and defining new putative primary disease mechanisms. Copyright © 2010 John Wiley & Sons, Ltd.