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Stress reactivity research has traditionally focused on the idea that exaggerated responses to stress may have adverse effects on health. Accumulating evidence suggests that attenuated responses to stress and delayed recovery may also be problematic.This review focuses on the role of the stress response of the hypothalamic-pituitary-adrenocortical axis, the endogenous opioid system, and the cardiovascular system in hypertension, pain perception, and addictive behaviors. Results from multiple methods of assessment and stress paradigms conducted in our laboratory over the past two decades are integrated with research from other investigators and with existing theories.Research indicates that exaggerated biological and physiological responses to stress and attenuated pain perception are associated with hypertension and risk for cardiovascular diseases. This research complements work linking reduced stress responses with enhanced pain sensitivity and discomfort. Multiple studies have also demonstrated that an attenuated stress response is linked to exacerbation of withdrawal symptoms and relapse in nicotine addiction. Evidence indicates important moderators (i.e., sex, personality traits, and early life adversity) and hypothalamic-pituitary-adrenocortical– and endogenous opioid system–related mechanisms in the altered response to stress. I integrate these findings in a conceptual model emphasizing that robust stress responses in the context of addiction and relapse should be considered as a marker of resiliency.A blunted stress response may indicate long-term physiological dysregulation that could usher harmful consequences for cardiovascular disease, pain perception, and addictive disorders. The impact of dysregulation is influenced by multiple individual and situational factors that should be considered in evaluating the clinical significance of stress response dysregulation.