A complex relationship exists between alcohol-drinking behavior and stress. Alcohol has anxiety-reducing properties and can relieve stress, while at the same time acting as a stressor and activating the body’s stress response systems. In particular, chronic alcohol exposure and withdrawal can profoundly disturb the function of the body’s neuroendocrine stress response system, the hypothalamic–pituitary–adrenocortical (HPA) axis. A hormone, corticotropin-releasing factor (CRF), which is produced and released from the hypothalamus and activates the pituitary in response to stress, plays a central role in the relationship between stress and alcohol dependence and withdrawal. Chronic alcohol exposure and withdrawal lead to changes in CRF activity both within the HPA axis and in extrahypothalamic brain sites. This may mediate the emergence of certain withdrawal symptoms, which in turn influence the susceptibility to relapse. Alcohol-related dysregulation of the HPA axis and altered CRF activity within brain stress–reward circuitry also may play a role in the escalation of alcohol consumption in alcohol-dependent individuals. Numerous mechanisms have been suggested to contribute to the relationship between alcohol dependence, stress, and drinking behavior. These include the stress hormones released by the adrenal glands in response to HPA axis activation (ie, corticosteroids), neuromodulators known as neuroactive steroids, CRF, the neurotransmitter norepinephrine, and other stress-related molecules.