Corticotrophin-releasing factor (CRF; interchangeable with corticotrophin-releasing hormone, CRH) is a neurohormone family of peptides which implements endocrine, physiological and behavioural responses to stressor exposure. Built-in biological diversity and selectivity of CRF system function is provided by multiple endogenous ligands and receptors which are heterogeneously distributed in both brain and peripheral tissues across species. At present, there are at least five distinct targets for CRF with unique cDNA sequences, pharmacology and localization. These fall into three distinct classes, encoded by three different genes and have been termed the CRF1 and CRF2 receptors and the CRF-binding protein. Significant gains in knowledge about the physiological role of CRF binding sites in brain have emerged recently due to the proliferation of novel, high-affinity, receptor-selective pharmacological tools as well as multiple knock-out and knock-in mutant mouse models. These results support a role for CRF binding sites in co-ordinating stress reactivity, emotionality and energy balance over the life-span of the organism.