Some aspects of drug abuse syndromes may be influenced by sensitization to some drug effects. This enhancement of drug effect has been associated with prior drug exposure and with exposure to stressful stimuli. It has been postulated that sensitization to psychomotor stimulant drug effects influences sensitivity to drug reward. The drugs of abuse best characterized for sensitization phenomena include cocaine, amphetamine, and morphine. In general, ethanol's molecular mechanisms of action have been difficult to define relative to drugs with known receptor or transporter binding sites and, likewise, ethanol sensitization has been less thoroughly examined. Evidence supporting the existence of behavioral sensitization to ethanol, for genetic differences in the occurrence of ethanol sensitization, and for the influence of corticosterone on the development of ethanol sensitization is reviewed herein. There appear to be different genetic determinants of acute drug sensitivity and sensitization. Cross-sensitization between stress and ethanol suggest a potential role for hypothalamic-pituitary-adrenal (HPA) axis associated changes in ethanol sensitization, consistent with mechanisms likely contributing to sensitization to other abused drugs. Furthermore, glucocorticoid receptors appear to mediate both ethanol- and stress-induced sensitization to ethanol. A biological link between drug reward and drug sensitization involving HPA axis hormones may exist and, thus, study of the sensitization process may elucidate mechanisms relevant to drug abuse.