Abstract Our program of research focuses on shame as a key emotional response to “social self” threats (i.e., social evaluation or rejection). We propose that shame may orchestrate specific patterns of psychobiological changes under these conditions. A series of studies demonstrates that acute threats to the social self increase proinflammatory cytokine activity and cortisol and that these changes occur in concert with shame. Chronic social self threats and persistent experience of shame-related cognitive and affective states predict disease-relevant immunological and health outcomes in HIV. Across our laboratory and longitudinal studies, general or composite affective states (e.g., distress) are unrelated to these physiological and health outcomes. These findings support a stressor- and emotional response-specificity model for psychobiological and health research.