Melanophore stimulating hormone (MSH) secretion from the vertebrate pars intermedia is regulated as for other pituitary hormones, by the hypothalamus. Removal of the pituitary from hypothalamic control results in an autonomous uninhibited secretion of MSH. Thus, as for prolactin, the hypothalamus exerts a tonic inhibitory control over MSH secretion. The nature of this inhibitory mechanism is presently being debated with two general models being considered. It is suggested by some investigators that peptides of neurohypophysial hormone origin act as MSH releasing and inhibiting factors (MRF' and MIF's, respectively). In this scheme, the neurohypophysial hormones such as oxytocin would serve as prohormones which by enzymatic cleavage by hypothalamic enzymes would yield MSH releasing and/or inhibiting factors. It is suggested that the terminal tripeptide side chain is an MIF whereas the N-terminal pentapeptide sequence of oxytocin is an MRF. The data supporting this hypothesis comes from work of a few investigators that espouse this scheme. To our knowledge, the so-called MSH releasing and inhibiting factors have proven ineffective in the hands of all other investigators in regulating MSH release.