Advances in genomics and neuroscience have ushered in unprecedented opportunities to increase our understanding of the biological underpinnings of mental disorders, yet there has been limited progress in translating knowledge on genetic risk factors to reduce the burden of these conditions in the population. We describe the challenges and opportunities afforded by the growth of large-scale population health databases, progress in genomics, and collaborative efforts in epidemiology and neuroscience to develop informed population-wide interventions for mental disorders. Future progress is likely to benefit from the following efforts: expansion of large collaborative studies of mental disorders to include more systematically ascertained multiethnic samples from biobanks and registries, harmonization of phenotypic characterization in registry and population samples to extend clinical diagnosis to transdiagnostic concepts, systematic investigation of the influences of both specific and nonspecific environmental factors that may combine with genetic susceptibility to confer increased risk of specific mental disorders, and implementation of study designs that can inform gene–environment interactions. Such data can ultimately be combined to develop comprehensive models of risks of, interventions for, and outcomes of mental disorders. With its focus on phenotypic characterization, sampling, study designs, and analytic methods, epidemiology will be central to progress in translating genomics to public health.