The susceptibility of developing most major psychiatric disorders is determined in part by contributions from risk alleles at multiple genetic loci. The central aim of this article is to highlight evidence from studies of neurodegenerative disorders suggesting that some of these alleles are shared by more than one psychiatric disorder, and to explore mechanisms that may underly these pleiotropic effects. The identification of constellations of susceptibility alleles associated with particular mental disorders will provide opportunities for new insights into the molecular and cellular pathophysiology of these disorders, and will have a major impact on psychiatric research and clinical care. This approach to reducing the variance in etiopathogenesis is also likely to be important for achieving the optimal use of available treatments (maximizing effectiveness and minimizing side effects), and for the discovery of novel medications or other interventions.