The corticotropin releasing factor (CRF) system coordinates a wide range of stress responses and has been implicated in the etiology of a number of clinical disorders. It is made up of a complex array of interactive peptides that interact with many other neurotransmitter and neuromodulatory systems. Dysregulation of CRF system signaling may be a common molecular pathway for the myriad "stress-related" disorders. Understanding the signaling and circuitry affected by this system is essential to understanding these psychiatric disorders. The extremely wide range of behaviors and physiological processes mediated by this system and the complexity of its signaling make this a difficult taskespecially to successfully target it for pharmacotherapy. In this review, we describe the molecular signaling of the CRF system and its interaction with other key neurotransmitter systems. Its role in a range of psychiatric disorders and potential as a target for therapeutic intervention will also be discussed.