Depression can be a consequence of medical illness and disability, yet recent literature suggests it may also influence morbidity and mortality through a variety of behavioral and biological mediators. Relatively little is known about the complex temporal relations among behavior, affect, motivation, and pathophysiology to account for the association between depression and mortality. We performed a systematic review of the recent literature (1997-2001) examining the evidence linking depression to non-suicide mortality, describe possible mediators of the depression mortality effect, and identify important next steps in this area of research, including: a) the development of well-specified a-priory mediator models that articulate how depression leads to mortality; b) the conduct of longitudinal studies in which depression and behavioral and pathophyisological mediators are assessed simultaneously; c) treatment studies for depression that include assessments of associated changes in health-related quality of life, medical morbidity, and mortality; and d) treatment studies for behavioral risk factors and medical conditions that include assessment of depressive symptoms.