Some important issues in substance abuse are the relationship between propensity to self-administer a drug and neurosensitivity to that drug; similarities and differences between various models of drug-seeking behavior; and the commonality of drug-seeking behavior across drugs and genotypes. Findings related to these issues are now emerging from the areas of pharmacogenetics and operant drug self-administration. Ethanol has been readily established as a positive reinforcer in AA (Alcohol Accepting), P (Preferring) and LEWIS rats, as well as C57BL/6J and LS/Ibg mice. In low ethanol preferring F344 and NP (Non-Preferring) rats, ethanol maintains significant but low levels of responding. Ethanol does not maintain lever-pressing behavior in BALB/cJ or SS/Ibg mice, and is avoided in DBA/2J mice. This pattern of reinforcement from ethanol is only moderately correlated with ethanol preference, and is not correlated with neurosensitivity to ethanol, at least as measured by duration of loss of the righting reflex (LORR). However, these genotypic patterns of reinforcement from ethanol do appear to correlate highly with patterns of reinforcement from cocaine and opiates. From these findings it is concluded that: 1) there exist important genetic determinants of drug reinforced behavior; 2) ethanol preference is not a highly accurate measure of reinforcement from ethanol; 3) sensitivity to ethanol as measured by LORR and self-administration of this drug are not highly genetically correlated; and 4) drug-seeking behaviors maintained by ethanol, cocaine and opiates may have at least some common biological determinants.