Relapse to drug use following abstinence is a significant impediment in the long-term treatment of drug abuse and dependence. Conditioned stimuli are believed to be critically involved in activating drug craving and relapse to compulsive drug-taking behavior. Studies in humans and animal models have recently begun to identify the fundamental neural circuitry that mediates relapse following withdrawal from chronic drug self-administration. The current review summarizes key findings in this area that have converged on the amygdalar complex and regions of the frontal lobe as critical structures in conditioned-cued relapse. It is proposed that the amygdala is a key regulator of discrete stimulus-reinforcer associations, while the anterior cingulate and orbitofrontal cortex are critical regulators of relapse evoked by conditioned stimuli that predict drug availability. This corticolimbic circuitry may form the neural basis of multiple long-term conditioned associations produced by a variety of drugs of abuse ranging from psychostimulants to opiates. Future studies aimed at discerning the functional roles of these pathways will provide critical direction for the development of treatments for the prevention of relapse.