Stress is both a critical contributor and consequence of substance use disorder (SUD). First, exaggerated subjective stress responses are characteristic of affective symptomatology such as depression, bipolar disorder, generalized anxiety, and posttraumatic stress disorder (sometimes stemming from histories of abuse) that have been prognostic of development of addiction in longitudinal studies. Substance use is negatively reinforced in many at-risk and addicted individuals because it may acutely alleviate stress. Second, chronic administration of commonly abused substances alters physiological stress response systems, especially during acute withdrawal. Third, acute stress responses blunt the addicted individual’s frontocortically mediated behavioral repertoire (solution space) in favor of reflexive behavioral biases toward relief-based substance use. Therefore, acute stress responses are a strong trigger for relapse to substance use during extended recovery. These findings have collectively led to approaches to SUD relapse prevention that pharmacologically blunt components of the stress response, but these agents have not reliably shown success in human clinical trials. This chapter reviews these different relationships between stress and addiction and offers future avenues for additional research.