CRF, CRF-related peptides and CRF receptors constitute a complex physiological system which has a key role in facilitating the adaptation of the organism to the stressful stimuli of the environment. The behavioral, endocrine, autonomic and immune branches of stress response are considered to be under the coordinating effects of CRF and its related peptides. The effects of these peptides are mediated through two distinct receptors, types 1 and 2 CRF receptors (CRF1 and CRF2). The two receptors are encoded by separate genes and belong to the G-coupled receptor superfamily. The wide influence of the CRF system on physiological processes in both brain and periphery, suggests the implication of the respective peptides in the pathophysiology of numerous disorders which involve dysregulated stress responses. The potential use of CRF antagonists in such disorders is currently under intense investigation. Furthermore, such compounds have been invaluable in elucidating the physiology of the CRF system. This review will focus on existing data on the structural and pharmacological characteristics as well as the experimental and potential clinical uses of non-peptide, small molecule CRF antagonists.