Corticotrophin-releasing factor (CRF) is the key mediator of the central nervous system response needed to adapt to stress. If adaptation fails, hypersecretion of CRF continues and produces, via CRF type 1 receptors, symptoms pertaining to cognition, appetite, sleep and anxiety, implicating CRF as a causal factor in affective disorders. Clinical studies with CRF receptor 1 antagonists support a novel pharmacological strategy for treating stress-related disorders. Here we summarize recent information obtained on CRF receptor 1 signaling and propose the concept of a more focused pharmacological intervention based on the signaling pathways involved. Recent findings suggest that CRF activates, via the same CRF receptor 1, different signaling pathways in specific areas of the brain. This intracellular and neuroanatomical signaling specificity will facilitate the search for less pleiotropic antagonists and new chemical compounds that modulate signal transduction in a site-specific manner.