Since CRF was discovered, three other peptides (the urocortins: UCN I, UCN II and UCN III), two different binding sites (the receptors: CRFR1 and CRFR2) and one binding protein (CRF-BP) have been described as members of the same family. Though there is no doubt about the roles of CRF and CRFR1 in the activation of HPA axis, there is still a debate about the roles of the UCNs and CRFR2 in the regulation of stress response. Previous studies have been demonstrated that CRF and UCN I (both acting through CRFR1) elevated the striatal DA and amygdalar GABA release in rats, but UCN II and UCN III (both binding to CRFR2) were ineffective on these extrahypothalamic neurotransmitters. The present study investigates and discusses the effects of physiological and pharmacological doses of UCNs on pituitary corticosterone release. In rats, under basal condititions CRF and UCN I induced dose-dependent increases of corticosterone levels in similar manner, while UCN II and UCN III produced bell-shaped dose-response curves, with lower doses decreasing and higher doses increasing the hormone levels. Future studies are yet to determine whether these changes in pituitary corticosterone release are initiated or associated by releases of hypothalamic neurohormones, such as CRF or AVP. However, we speculate that CRFR2 receptor have important, but multifactorial role in the modulation of the stress response and UCNs are significant, but variable fine-tuners of the HPA axis.