Recent advances in mammalian genomics are providing unprecedented opportunities to identify genes that influence neural systems relevant to psychiatric illnesses. As a genetically tractable mammalian species in which complex behaviors may be modeled, mice have been the focus of much attention for examining relationships between genes and behavior. Many investigators are pursuing experimental strategies in which the functions of known genes are examined by studying the impact of their manipulation in mice. These studies are providing important information regarding genetic influences on behavior, as well as animal models relevant to human disease processes. Additional powerful genetic strategies have recently been initiated to search broadly for genes that influence particular clinically relevant behavioral traits. These approaches promise to uncover a large number of novel genetic influences on neuronal pathways that regulate behavior. In this review, mouse molecular genetic techniques are described and illustrative examples of their application to neurobehavioral processes relevant to clinical disorders are provided. Future directions in technology development that promise to further enhance the utility of these approaches for translational research are also described.