Hypothalamic corticotropin releasing hormone (CRH) exerts its diverse physiological actions via cell surface G protein-coupled CRH receptors (CRHRs), of which two subtypes (CRHR1 and CRHR2) have been identified. CRH regulates pituitary ACTH secretion and mediates behavioral and autonomic responses to stress. Overproduction of CRH and stress system abnormalities are associated with psychiatric diseases such as depression, anxiety, eating disorders, and addiction. CRHR1 is expressed in pituitary corticotrophs and the brain. CRH binds to CRHR1 with high affinity, and activation of CRHR1 by CRH increases cAMP intracellular levels and activates protein kinase A. CRHR1 also couples to activation of MAPK as well as protein kinase C in an isoenzyme-specific manner. Selective CRHR1 antagonists offer new possibilities for the treatment of anxiety and depression.