Corticotropin-Releasing Hormone (CRH) or Corticotropin-Releasing Factor (CRF) and its family of related naturally occurring endogenous peptides and receptors are becoming recognized for their actions within central (CNS) and peripheral (PNS) nervous systems. It should be recognized that the term 'CRH' has been displaced by 'CRF' [Guillemin, R., 2005. Hypothalamic hormones a.k.a. hypothalamic releasing factors. J. Endocrinol. 184, 11-28]. However, to maintain uniformity among contributions to this special issue we have used the original term, CRH. The term 'CRF' has been associated recently with CRH receptors and designated with subscripts by the IUPHAR nomenclature committee [Hauger, R.L., Grigoriadis, D.E., Dallman, M.F., Plotsky, P.M., Vale, W.W., Dautzenberg, F.M., 2003. International Union of Pharmacology. XXXVI. Corticotrophin-releasing factor and their ligands. Pharmacol. Rev. 55, 21-26] to denote the type and subtype of receptors activated or antagonized by CRH ligands. CRH, as a hormone, has long been identified as the regulator of basal and stress-induced ACTH release within the hypothalamo-pituitary-adrenal axis (HPA axis). But the concept, that CRH and its related endogenous peptides and receptor ligands have non-HPA axis actions to regulate CNS synaptic transmission outside the HPA axis, is just beginning to be recognized and identified [Orozco-Cabal, L., Pollandt, S., Liu, J., Shinnick-Gallagher, P., Gallagher, J.P., 2006a. Regulation of Synaptic Transmission by CRF Receptors. Rev. Neurosci. 17, 279-307; Orozco-Cabal, L., Pollandt, S., Liu, J., Vergara, L., Shinnick-Gallagher, P., Gallagher, J.P., 2006b. A novel rat medial prefrontal cortical slice preparation to investigate synaptic transmission from amygdala to layer V prelimbic pyramidal neurons. J. Neurosci. Methods 151, 148-158] is especially noteworthy since this synapse has become a prime focus for a variety of mental diseases, e.g. schizophrenia [Fischbach, G.D., 2007. NRG1 and synaptic function in the CNS. Neuron 54, 497-497], and neurological disorders, e.g., Alzheimer's disease [Bell, K.F., Cuello, C.A., 2006. Altered synaptic function in Alzheimer's disease. Eur. J. Pharmacol. 545, 11-21]. We suggest that "The Stressed Synapse" has been overlooked [c.f., Kim, J.J., Diamond, D.M. 2002. The stressed hippocampus, synaptic plasticity and lost memories. Nat. Rev., Neurosci. 3, 453-462; Radley, J.J., Morrison, J.H., 2005. Repeated stress and structural plasticity in the brain. Ageing Res. Rev. 4, 271-287] as a major contributor to many CNS disorders. We present data demonstrating CRH neuroregulatory and neuromodulatory actions at three limbic synapses, the basolateral amygdala to central amygdala synapse; the basolateral amygdala to medial prefrontal cortex synapse, and the lateral septum mediolateral nucleus synapse. A novel stress circuit is presented involving these three synapses. We suggest that CRH ligands and their receptors are significant etiological factors that need to be considered in the pharmacotherapy of mental diseases associated with CNS synaptic transmission.