In vivo model systems are a critical tool for gaining insight into the pathology underlying psychiatric disorders. Although modern functional imaging tools allow study of brain correlates of behavior in clinical groups and genome-wide association studies are beginning to uncover the complex genetic architecture of psychiatric disorders, there is less understanding of pathology at intervening levels of organization. Several psychiatric disorders derive from pathological neural plasticity, and studying the mechanisms that underlie these processes, including reinforcement learning and spike-timing-dependent plasticity, requires the use of animals. It will be particularly important to understand how individual differences in plasticity mechanisms at a cellular level confer resilience on some but lead to disease in others.