Cocaine- and amphetamine-regulated transcript (CART) peptides are novel neurotransmitters that are implicated in several physiological functions such as control of feeding behavior, drug reward, sensory processing, stress, and development. Although a majority of studies have examined the role of CART in the brain, less is known about its function in the periphery. Therefore, the goals of this study were to examine the levels and species of CART peptides in blood, to determine whether they undergo diurnal rhythms, and to elucidate their sources and regulatory factors. RIA showed that CART peptides are present in the blood of rats and monkeys and that they exhibit a diurnal variation. Western blotting confirmed the pattern of diurnal variation in rats and, additionally, showed that CART immunoreactivity was due to a single predominant fragment with an apparent molecular weight in the range of the active CART 55-102 peptide. Adrenalectomy caused a 70% reduction in CART peptide levels in rat blood, and this was reversed by corticosterone replacement. CART levels paralleled glucocorticoid levels in rat and monkey blood. Control of CART levels by corticosterone suggests the possibility that CART peptides in blood may be influenced by hypothalamic-pituitary-adrenal interactions and that they may play a role in glucocorticoid-related processes such as stress.