This article will review data obtained from both clinical and preclinical investigations demonstrating that exposure to stress has a significant impact on drug addiction. The preclinical literature suggests that stress increases reward associated with psychomotor stimulants, possibly through a process similar to sensitization. While it is not conclusive that a similar process occurs in humans, a growing clinical literature indicates that there is a link between substance abuse and stress. One explanation for the high concordance between stress-related disorders and drug addiction is the self-medication hypothesis, which suggests that a dually diagnosed person often uses the abused substance to cope with tension associated with life stressors or to relieve symptoms of anxiety and depression resulting from a traumatic event. However, another characteristic of self-administration is that drug delivery and its subsequent effects on the hypothalamo-pituitary-adrenal (HPA) axis are under the direct control of the individual. This controlled activation of the HPA axis may result in the production of an internal state of arousal or stimulation that is actually sought by the individual (i.e., the sensation-seeking hypothesis). During abstinence, exposure to stressors or drug-associated cues can stimulate the HPA axis to remind the individual about the effects of the abused substance, thus producing craving and promoting relapse. Continued investigations into how stress and the subsequent activation of the HPA axis impact addiction will result in the identification of more effective and efficient treatment for substance abuse in humans. Stress reduction, either alone or in combination with pharmacotherapies targeting the HPA axis may prove beneficial in reducing cravings and promoting abstinence in individuals seeking treatment for addiction.