Research advances over the past four decades have demonstrated that a significant proportion of people with alcohol use disorders also suffer from a comorbid mood or anxiety disorder. This article briefly reviews the associations among alcohol dependence, major depressive disorder, and posttraumatic stress disorder. Dysregulation of the brain's and body's stress system (i.e., the limbic-hypothalamic- pituitary-adrenal axis) might serve as a common mechanistic link to explain some of the relationships among these frequently comorbid conditions. Finally, the article examines the role of sex differences in stress circuitry. These differences may explain why men and women differ in their risk for developing comorbid alcoholism and stress-related disorders.