Abstract: Depressive symptoms are common among patients with cancer, and both psychological stress and physiological factors have been implicated in the etiology of depression. Scientific progress in this area is challenged by the changing nature of psychological and physiological processes over the course of cancer diagnosis and treatment. The article by Wu and colleagues in the current issue of Psychosomatic Medicine provides an example of thoughtful consideration of the complex longitudinal relationships between psychological stress, physiology, and depressive symptoms. These findings are put into context by discussing broader challenges in this area, with a focus on the contribution of inflammatory processes caused by cancer and/or its treatment to depressive and related sickness behavior symptoms. We outline several regulatory pathways by which cortisol, inflammatory processes, and depressive symptoms may interact in the context of cancer and highlight implications of these interactions for tumor progression. Additional research is needed to delineate these pathways and advance scientific understanding of the biobehavioral mechanisms underlying depressive symptoms in the context of cancer, with important implications for the development of effective interventions for patients undergoing initial cancer treatment, as well as for long-term survivors.