Recent studies suggest a significant biological contribution to posttraumatic stress disorder (PTSD). In particular, central catecholamine and endogenous opioid systems have been implicated both in this syndrome and in substance abuse. We review relevant animal and human studies that support these hypotheses and suggest that this overlap may contribute to the incidence of substance abuse in PTSD. The animal studies have primarily employed the learned helpless and conditioned emotional response models and have included assessments of brain catecholamines, locus ceruleus activity, and behavioral correlates in rodents and nonhuman primates. Human studies have used only indirect measures to assess these variables. However, both therapeutic approaches and attempts at self-medication for PTSD have supported this hypothesis.