Major depression is a consequential public health problem in the United States. Depression has long been recognized as an important target of intervention in psychology and psychiatry, but these fields have focused efforts primarily on treatment rather than prevention. Although effective preventive interventions targeting high-risk groups have been developed, they have thus far had poor reach and sustainability in the community. The development of sustainable preventive interventions that have the potential to impact population health represents a critical goal for the field. To this end, a research agenda incorporating the perspectives of both mental health disciplines and public health is proposed as a guide for future depression prevention research. Increased interdisciplinary collaboration between mental health disciplines and public health is recommended to develop, enact, and evaluate multilevel preventive interventions aimed at reducing the population health burden of major depression.