Addiction to alcohol or other drugs (AODs) is a complex problem determined by multiple factors, including psychological and physiological components. Stress is considered a major contributor to the initiation and continuation of AOD use as well as to relapse. Many studies that have demonstrated an association between AOD use and stress have been unable to establish a causal relationship between the two. However, stress and the body's response to it most likely play a role in the vulnerability to initial AOD use, initiation of AOD abuse treatment, and relapse in recovering AOD users. This relationship probably is mediated, at least in part, by common neurochemical systems, such as the serotonin, dopamine, and opiate peptide systems, as well as the hypothalamic-pituitary-adrenal (HPA) axis. Further exploration of these connections should lead to important pharmacological developments in the prevention and treatment of AOD abuse. Studies indicate that treatment techniques which foster coping skills, problem-solving skills, and social support play a pivotal role in successful treatment. In the future, individualized treatment approaches that emphasize stress management strategies in those patients in whom a clear connection between stress and relapse exists will become particularly important.