The etiology of substance use disorders is related to changes in neuronal systems involved in reward anticipation, negative affect, and withdrawal, as well as to alterations in inhibition and executive control. Genetic and epigenetic variation associated with individual differences in these mechanisms may be important for predicting the effectiveness of current treatments and informing future pharmacogenomic investigations. Genetic research efforts have increasingly involved the use of approaches that leverage neurobiological phenotypes to link changes at the molecular level (e.g., genetic and epigenetic variation) to changes in intermediate neuroimaging phenotypes, and ultimately to clinical outcomes. The current review summarizes recent efforts that utilize neuroimaging and genetic approaches in the context of a three-stage model of addiction. In addition, this review explores how these approaches have been used to study the progression from impulsive, recreational substance use to the compulsive, addicted state. Finally, this review describes future ways that research may incorporate these approaches to examine important stage-specific mechanisms of addiction.