The corticotropin-releasing factor (CRF)-like peptides, which include the mammalian peptides CRF, urocortin 1, urocortin 2, and urocortin 3, play an important role in orchestrating behavioral and physiological responses that may increase an organism's chance of survival when confronted with internal or external stressors. There is, however, evidence that a chronic overactivity of brain CRF systems under basal conditions may play a role in the etiology and maintenance of psychiatric disorders such as depression and anxiety disorders. In addition, there is evidence of a role for CRF-like peptides in acute and protracted drug abstinence syndromes and relapse to drug-taking behavior. This review focuses on the role of CRF-like peptides in the negative affective state associated with acute and protracted withdrawal from three widely abused drugs, cannabis, nicotine, and alcohol. In addition, we discuss the high comorbidity between stress-associated psychiatric disorders and drug dependence. A better understanding of the brain stress systems that may underlie psychiatric disorders, acute and protracted drug withdrawal, and relapse to drug-taking behavior may help in the development of new and improved pharmacotherapies for these widespread psychiatric disorders.