We investigated the endogenous opioid system and its role in mediating the reinforcing effects of ethanol that lead to high ethanol consumption as a biochemical marker of an individual's vulnerability to excessive ethanol consumption. We performed studies using human subjects with [high risk (HR)] and without [low risk (LR)] a family history of alcoholism to supplement our studies with experimental animals bred selectively for high- or low-ethanol consumption. HR subjects had lower basal plasma beta-endorphin levels as compared with LR subjects, but they had a more pronounced release of beta-endorphin after exposure to ethanol. Findings from animal studies indicated that ethanol-preferring (C57BL/6) mice (analogous to the HR human subjects) had higher levels of hypothalamic beta-endorphin activity than did ethanol-avoiding (DBA/2) mice (analogous to the LR human subjects) under basal conditions. However, the C57BL/6 mice had a more pronounced release of hypothalamic beta-endorphin than did DBA/2 mice after exposure to ethanol. Thus, although hypothalamic beta-endorphin system activity in human and animal models of alcoholism differs under basal conditions, there is enhanced hypothalamic beta-endorphin system activity after exposure to ethanol in both models. We have also performed studies comparing the density and distribution of opioid receptors in brains of ethanol-preferring animals, such as C57BL/6 mice and ALKO-alcohol (AA) rats, and ethanol-avoiding animals, such as DBA/2 mice and ALKO-non-alcohol (ANA) rats. Interestingly, it was observed that in distinct brain regions known to be important for mediating the process of reinforcement, the C57BL/6 mice had a higher density of delta-opioid receptors than the DBA/2 mice, while the AA rats had a higher density of mu-opioid receptors than the ANA rats. Thus, in the ethanol-preferring animals, the increased release of beta-endorphin following exposure to ethanol was associated with a higher density of delta- or mu-opioid receptors in brain regions important for reinforcement, such as the nucleus accumbens and the ventral tegmental area, and may interact with the dopaminergic system and promote ethanol's reinforcing properties, leading to excessive drinking and alcoholism.