Basic neurobiological studies have led to great progress in our understanding of the mechanisms of action of drugs of abuse. Much has been learned about the brain response from the moment a psychoactive drug enters the organism onwards, including the psychological, neurobiological and peripheral effects of repeated drug administration, withdrawal and re-exposure. However, to relate this knowledge to the human experience requires further research on the antecedents of drug-taking behavior and the factors that predispose particular individuals to drug seeking and drug abuse. Thus, it is important to address several issues at the fundamental level: (1) Why are some individuals more vulnerable to drugs of abuse more than others? Is there a broader dimension or dimensions of emotional reactivity that contribute to this difference in vulnerability? (2) What is the effect of psychosocial stress on drug-seeking and drug-taking behavior, and are the effects distinct across individuals? (3) Since both drug-taking behavior and stress have sustained and pervasive effects on the brain, can we use microarrays to discern the "neural signature" or "neural phenotype" associated with these processes, and can we distinguish this signature across individuals with differing propensities to taking drugs? In the present paper, we summarize some of our early attempts at addressing these questions. We rely on animal studies aimed at characterizing the emotional and stress reactivity of rats with different propensities to self-administer drugs (high responders and low responders); we briefly describe the effect of a psychosocial stressor on these animals; we then detail a study using microarray technology aimed at investigating the "neural phenotype" associated with social defeat stress in the high vs. low responder animals. This "discovery" approach is used as a starting place for identifying novel mechanisms that might alter the vulnerability of different individuals to drug-seeking behavior. The power and limits of this approach, and its future directions, are discussed within this general framework.