Corticotropin-releasing factor (CRF) is the primary physiological regulator of basal and stress-induced release of ACTH, beta-endorphin and other POMC-derived peptides from the pituitary and plays a major role in the brain and periphery in coordinating endocrine, electrophysiological, autonomic, behavioral and immune responses to stress. In addition, recent clinical data implicate CRF in the etiology and pathophysiology in a variety of endocrine, psychiatric and neurodegenerative disorders. The various effects of CRF are mediated by two distinct CRF receptors expressed at high levels in selected brain areas, but also at different levels in several other non-neuronal tissues. This chapter provides an overview of the current knowledge about CRF receptors including tissue specificity and regulatory aspects as well as molecularbiological, biochemical and pharmacological characteristics. In addition, neuroimmune, neuroendocrine and behavioral-related implications of the CRF receptor as well as its involvement in a variety of disorders are discussed. This review summarizes four decades of research beginning with the search for the factor that governs the release of ACTH and getting to the recent findings including the successful cloning of different receptor subtypes and the discovery of a new endogenous CRF-related ligand.