Neuropsychiatric disease represents the ideal class of disease to assess the role of epistasis, as more genes are expressed in the brain than in any other tissue. In this chapter, two well-studied neuropsychiatric diseases are examined, Alzheimer's disease (AD) and schizophrenia, which have been shown to have multiple and, often, replicated interactions that associate with clinical endpoints or related phenotypes. In each case, a single gene is represented in a plurality of epistatic interactions, apolipoprotein E (APOE) for AD and catechol-O-methyltransferase for schizophrenia. Interestingly, of the two, only APOE has clear-cut and consistent evidence for a marginal association. Unraveling the underlying reasons is important in understanding both genetic etiology and architecture as well as how to use genetics to provide better personalized treatments.