Two distinct sub-types of receptor encoded by separate genes have been described to date, CRF1 and CRF2, and they belong to the Class-B subdivision within the G-protein coupled receptor (GPCR) super family. All known CRF receptors positively regulate the accumulation of cAMP in response to CRF and are therefore coupled to Gs as the major signal transduction mechanism. CRF receptors interact with two sub-families of CRF peptide ligands - mammalian hypothalamic CRFs and urocortin and secondly, non-mammalian peptides like sauvagine (frog) and urotensin-I (fish). The CRF peptide backbone tends to form one a-helical secondary structure in the central portion of the molecule, whereas the N-terminal and C-terminal regions of the peptide are not structured. Residues 1 - 8 at the N-terminal of the peptide are critical for activation of the receptor, whereas residues 11 - 41 at the C-terminal of the peptide are important for binding, especially to the N-terminal extracellular domain of the receptor. Using both agonist and antagonist peptides and heterocyclic-based antagonists combined with strategically mutated receptors, it has been possible to define binding sites located on the extracellular surface (for peptides) and within the helical domains (for the non-peptides) of the protein. There is a significant positive correlation between specific measures of CRF activation in the central nervous system and the incidence of disorders associated with the stress axis. These effects range from neuropsychiatric disorders such as anxiety or depression to somatic disorders such as dysregulation of the immune system or modulation of gastric function. The tremendous effort being put forth into the identification of high affinity, selective, safe and tolerable drug candidates acting on CRF receptors holds promise for novel therapies for some of these disorders.