We have shown that intracerebroventricular administration of the corticotropin-releasing factor (CRF) receptor antagonist D-Phe CRF(12-41), blocks footshock-induced reinstatement of drug seeking in cocaine-trained rats. We now report that D-Phe acts in the bed nucleus of the stria terminalis (BNST), and not in the amygdala, to block footshock-induced reinstatement of cocaine seeking. In addition, CRF injections in the BNST, and not in the amygdala, are sufficient to reinstate cocaine seeking. Rats were trained to self-administer cocaine intravenously on a fixed ratio (FR-1) schedule of reinforcement. After 5 drug-free days, animals were returned to the self-administration chambers and given daily extinction and reinstatement test sessions. To test the effects of D-Phe CRF(12-41) on stress-induced reinstatement, rats were pretreated with vehicle or D-Phe in either the BNST (10 or 50 ng per side) or amygdala (50 or 500 ng per side) before being exposed to 15 min of intermittent footshock stress. To test whether injections of CRF itself could induce reinstatement, rats were given vehicle or CRF in either the BNST (100 or 300 ng per side) or amygdala (300 ng per side) 15 min before the session. Injections of D-Phe into the BNST completely blocked footshock-induced reinstatement of cocaine seeking; injections of CRF itself in this structure induced reinstatement. Injections of these compounds into the amygdala were without effect. These findings suggest that activation of CRF receptors in the BNST, but not in the amygdala, is critical for footshock-induced reinstatement of cocaine seeking.