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Research over the past several decades has documented psychosocial influences on the development and progression of several major medical illnesses. The field is now increasingly focused on identifying the biological and behavioral mechanisms underlying these effects. This review takes stock of the knowledge accumulated in the biological arena to date and highlights conceptual and methodological approaches that have proven especially productive. It emphasizes the value of a disease-centered approach that “reverse engineers” adverse health outcomes into their specific biological determinants and then identifies psychologically modulated neuroendocrine and immunologic dynamics that modulate those pathological processes at the cellular and molecular levels.