Recent investigations in mouse lines either deficient for the CRH receptor 1 (CRHR1) or 2 (CRHR2) suggest that the CRH neuronal system may comprise two separate pathways that can be coordinately and inversely activated in stress-induced hypothalamic-pituitary-adrenal (HPA) response and anxiety-like behavior. We generated mice deficient for both CRHR1 (Crhr1(-/-)) and CRHR2 (Crhr2(-/-)) to investigate the HPA system regulation in the absence of known functionally active CRH receptors under basal conditions and in response to different ethologically relevant stressors. To elucidate possible gene dose effects on the action of both CRH receptors, our analysis included heterozygous and homozygous CRHR1- or CRHR2-deficient mice, mutants lacking both CRH receptors, compound mutants with homozygous and heterozygous deficiency for either of the receptors, and their wild-type littermates. Both male and female Crhr1(-/-)Crhr2(-/-) mutants were viable, fertile, and indistinguishable in size from wild-type littermates. We show that the endocrine phenotype of mice lacking both CRHRs is dominated by the functional loss of CRHR1. CRHR2 does not compensate for CRHR1 deficiency, nor does the lack of CRHR2 exacerbate the CRHR1-dependent impairment of the HPA system function. Within the intraadrenal CRH/ACTH system, our data suggest different roles for CRHR1 and CRHR2 in fine-tuning of adrenocortical corticosterone release.