The abuse of and addiction to drugs of abuse, such as tobacco, alcohol, opioids, and illicit drugs, are growing global problems that affect the welfare of individuals and societies worldwide. The National Institute of Drug Abuse estimates the annual cost of substance abuse to be over $740 billion in costs related to drug intoxication, withdrawal and relapse. A primary challenge in the treatment of substance abuse is the tendency of users to relapse following acute or extended periods of abstinence; on average over 60% of substance abusers will return to drug use within a year of receiving treatment, many relapsing following stressful life events. Central to the successful treatment of drug addiction is understanding the cellular mechanisms by which relapse episodes occur. Current data suggest that the activation of pituitary adenylate cyclase activating peptide (PACAP) systems in the bed nucleus of the stria terminalis (BNST) is an important event underlying stress-induced reinstatement to drug-seeking in a rodent model of stress-induced relapse. In conjunction with immunohistochemistry and pharmacological treatments, we used this behavioral model of stress-induced relapse to evaluate PACAP and PACAP type-1 receptor (PAC1-R) signaling in stress-induced reinstatement to cocaine seeking. Activation of the PAC1 receptor appears to be critical to stress-induced reinstatement, as the selective PAC1-R agonist, maxadilan, produced reinstatement behaviors in the absence of stress. Moreover, BNST pretreatment with either mitogen activated protein kinase-ERK (MEK) or endocytosis inhibitors to block extracellular signal-related kinase (ERK) signaling attenuated stress-induced reinstatement. Furthermore, BNST phosphorylated ERK (pERK) expression, mediated by PAC1-R activation, is substantially potentiated in cocaine-experienced animals after stressor exposure, in a manner that is dependent on endosomal signaling and MEK activity. These data suggest that the activation of a PAC1 signaling cascade is a key event underlying stress-induced reinstatement. Furthermore, this data may suggest a permanent change in the BNST PACAP system (sensitization) following cocaine exposure.