Corticotropin-Releasing Factor (CRF) affects catecholamine production both centrally and peripherally. Aim of the present work was to examine the presence of CRF, its related peptides, and their receptors in the medulla of human and rat adrenals and their direct effect on catecholamine synthesis and secretion. CRF, Urocortin I (UCN1), UCN2, and CRF receptor type I (CRF₁) and CRF₂ were present in human and rat adrenal medulla as well as in the PC12 pheochromocytoma cells by immunocytochemistry, immunofluorescence and RT-PCR. Exposure of dispersed human and rat adrenal chromaffin cells to CRF₁ receptor agonists induced catecholamine secretion in a dose-dependent manner, an effect peaking at 30 min while CRF₂ receptor agonists suppressed catecholamine secretion. The respective effects were blocked by CRF₁ and CRF₂ antagonists. CRF peptides affected catecholamine secretion via changes of subplasmaliminal actin filament polymerization. CRF peptides also affected catecholamine synthesis. In rat chromaffin and PC12 cells, CRF₁ and CRF₂ agonists induced catecholamine synthesis via tyrosine hydroxylase. However, in human chromaffin cells, activation of CRF₁ receptors induced tyrosine hydroxylase while activation of CRF₂ suppressed it. In conclusion, it appears that a complex intra-adrenal CRF-UCNs/CRF-receptor system exists in both human and rat adrenals controlling catecholamine secretion and synthesis.