Traditionally, research on childhood mood disorders has focused on clinical trials and longitudinal course and outcome studies, rather than on prevention. Recently, however, advances in the design, methodology, and evaluation of prevention approaches and progress in understanding what factors predispose children to depression have made possible the development of theoretically driven, empirically justified approaches to the prevention of depression in youngsters who are at high risk, either because of elevated symptom levels or parental mood disorder. In this review, we outline recent empirical findings on risk factors for depression in nonreferred samples of youngsters and also in children of depressed parents. Additionally, we review three trials of preventive interventions for childhood depression that yield promising initial findings. We emphasize the need to understand both risks for depression and factors that protect youngsters at risk from succumbing to depression in guiding the development of prevention programs. We also argue that consideration of prevention of depression requires addressing broader social adversity influences that lead to poor mental health outcomes in children, even beyond the effects of parental mood disorder. We conclude with an emphasis on the importance of a developmental-transactional perspective that highlights opportunities for intervention at different points across the lifespan.