Adrenocorticotropin (ACTH)-related compounds, termed melanocortins, produce a large number of effects on the central nervous system (CNS) after their peripheral administration. Some of the CNS effects of ACTH are mediated through the release of glucocorticoids from the adrenal gland, but there are fragments and analogues of ACTH that do not act on the adrenals. This raises the possibility that some blood-borne melanocortins may be acting directly on the brain, which would necessitate their crossing the blood-brain barrier (BBB). We review here the literature showing that melanocortins can affect the BBB in several ways, including an alteration of the permeability of the BBB to other substances.