Alcohol dependence is a chronic relapsing disorder characterized by neuroadaptations that may result in the emergence of negative affective states and stress responses upon discontinuation of alcohol use. Clinical studies have demonstrated that alcohol-dependent people are more sensitive to relapse provoking cues such as alcohol, negative affect, and stress. Moreover, stress relief during protracted abstinence is thought to be a major motivation for excessive alcohol consumption. The relationship between chronic alcohol use, stress, and relapse has implications for the treatment of alcohol dependence. Recent research suggests that neural systems mediating stress responses may offer useful targets for pharmacotherapy of alcoholism.