Intrinsic vulnerability is central to the transition of recreational drug use to misuse. Several factors contribute to vulnerability, inherent or acquired, and they account for the huge individual differences observed concerning the propensity to enter in the addiction process. Some of the multifactional causes for a vulnerable phenotype will be examined: genetic factors, age and gender influences, various comorbidities and epidemiological observations. Stress-induced vulnerability will be particularly reviewed because it provides a good model for a pathophysiological research and for relating environmental events to biological consequences of drug vulnerability, namely through the striato-cortical dopamine system. Experimental studies are generally blind concerning these historical factors that contribute vulnerability and a critical evaluation of current animal models is needed. The transition of the last stage of the process, addiction, is conceptualized as a progression from homeostasis to allostasis and then, to pathology.