Dysfunctioning of corticotropin-releasing factor (CRF) and its receptors (CRF1 and CRF2) has been linked to the development of stress-related disorders, such as affective disorders and drug abuse. The molecular characterization of CRF1 and CRF2 receptors and their splice variants has generated detailed information on their pharmacology, tissue distribution and physiology. In addition, the recent development of a small molecule CRF1 antagonist has provided important information on the contribution of this receptor to the development of stress-related diseases. Despite the high homology to the CRF1 receptor and the generation of peptide-based research tools, the physiological role of the CRF2 receptor is largely unclear. This is due to different expression patterns in rodents and primates and the lack of brainpenetrant CRF2-selective small molecule antagonists. However, the CRF2 receptor may be important for motivational types of behavior essential for survival, such as feeding and defense and impacts on cardiovascular function.