Despite the prevalence and public health impact of substance use disorders (SUDs), effective long-term treatments remain elusive. Aerobic exercise is a promising, nonpharmacological treatment currently under investigation as a strategy for preventing drug relapse. Aerobic exercise could be incorporated into the comprehensive treatment regimens for people with substance abuse disorders. Preclinical studies of SUD with animal models have shown that aerobic exercise diminishes drug-seeking behavior, which leads to relapse, in both male and female rats. Nevertheless, little is known regarding the effects of substance abuse-induced cellular and physiological adaptations believed to be responsible for drug-seeking behavior. Accordingly, the overall goal of this review is to provide a summary and an assessment of findings to date, highlighting evidence of the molecular and neurological effects of exercise on adaptations associated with SUD.