Abstract It has been suggested that a substantial portion of the heritable genetic component of schizophrenia risk reflects gene–gene interactions (“epistasis”) rather than simply the cumulative effect of multiple independent genes. However, clinical studies of epistatic interactions require considerable statistical power and place prohibitive demands on sample size. The use of preclinical genetic models provides a feasible and complementary model to study the role of epistatic gene effects in the pathogenesis of schizophrenia. This review summarizes recent genetic and human neuroimaging evidence for epistasis between genes associated with increased risk for schizophrenia. Also discussed is the evidence from existing preclinical studies which have described convergent and divergent phenotypes arising from independent or simultaneous mutation of prominent genetic risk factors for schizophrenia.