Publisher Summary The chapter discusses the role of genes in the etiology of mood disorders. The effects of genes may be direct and indirect such as modulation of the effects of early life stress as well as current stress. Stress, particularly in early life, also contributes to the risk for mood disorders. Different types of stressful events have been found to increase risk for depressive episodes. There are gender differences in reactivity to stressful life events, with women more likely to experience a depressive episode in relation to stress connected with social networks and interaction, and men in relation to work, or divorce or separation. Vulnerability to the depressogenic effects of stress is also thought to have genetic underpinnings. Individuals with greater genetic liability for mood disorders are more likely to experience onset of a depressive episode in response to a stressful life event than those with no genetic liability. Although there are many gaps in the current knowledge, a model is emerging in which early life stress can interact with genetic vulnerability to lead to increased risk for mood disorders. This emerging model also identifies targets for both pharmacologic and psychosocial intervention and has greater potential for prevention than previous therapeutic approaches that have focused on treatment of acute episodes of major depression or mania or prevention of recurrent episodes. Further treatments may target effects of early childhood stress in at-risk individuals.