Urocortin (UCN) 1, 2, and 3 are members of the corticotropin-releasing factor (CRF) family that display varying affinities to the CRF receptor 1 (CRFR1 (CRHR1)) and 2 (CRFR2 (CRHR2)). UCNs represent important modulators of stress responses and are involved in the control of anxiety and related disorders. In addition to the CNS, UCNs and CRFRs are highly expressed in several tissues including the adrenal gland, indicating the presence of UCN-dependent regulatory mechanisms in these peripheral organ systems. Using knockout (KO) mouse models lacking single or multipleUcngenes, we examined the potential role of the three differentUcns on morphology and function of the adrenal gland. Adrenal morphology was investigated, organ size, cell size, and number were quantified, and growth kinetics were studied by proliferative cell nuclear antigen staining andCcnd1expression analysis. Furthermore, mRNA expression of enzymes involved in steroidogenesis and catecholamine synthesis was quantified by real-time PCR. Following this approach,Ucn2,Ucn1/Ucn2dKO andUcn1/Ucn2/Ucn3tKO animals showed a significant cellular hypotrophy of the adrenal cortex and an increase inCcnd1expression, whereas in all other genotypes, no changes were observable in comparison to age-matched controls. For steroidogenesis,Ucn2/Ucn3dKO animals displayed the most pronounced changes, with significant increases in all investigated enzymes, providing indirect evidence for increased stress behavior. Taken together, these data suggest that mainlyUcn2andUcn3could be involved in adrenal stress response regulation whileUcn2additionally appears to play a role in morphology and growth of the adrenal gland.