Addiction inflicts large personal, social, and economic burdens, yet its etiology is poorly defined and effective treatments are lacking. As with other neuropsychiatric disorders, addiction is characterized by a core set of symptoms and behaviors that are believed to be influenced by complex gene-environment interactions. Our group focuses on the interaction between early stress and genetic background in determining addiction vulnerability. Prior work by our group and others has indicated that a history of prenatal stress (PNS) in rodents elevates adult drug seeking in a number of behavioral paradigms. The focus of the present chapter is to summarize work in the area of PNS and addiction models as well as our recent studies of PNS on drug seeking in different strains of mice as a strategy to dissect gene-environment interactions underlying cocaine addiction vulnerability. These studies indicate that ability of PNS to elevate adult cocaine seeking is strain dependent. Further, PNS also alters other nondrug behaviors in a fashion that is dependent on different strains and independent from the strain dependence of drug seeking. Thus, it appears that the ability of PNS to alter behavior related to different psychiatric conditions is orthogonal, with similar nonspecific susceptibility to prenatal stress across genetic backgrounds but with the genetic background determining the specific nature of the PNS effects. Finally, the advent of recombinant inbred mouse strains is allowing us to determine the genetic bases of these gene-environment interactions. Understanding these effects will have broad implications to determining the nature of vulnerability to addiction and perhaps other disorders.