The new data reported here, and available in the literature, are interpreted to indicate that acute release of PRL in stress is probably mediated by secretion of VIP and PHI arising from a subpopulation of paraventricular cells in the tuberoinfundibular system, and that this secretion is under serotonergic control, presumably by way of the raphe nuclear projection to the hypothalamus. The acute PRL response to suckling response is only partially under VIP/PHI control, and may be regulated by an as yet unidentified neural lobe hormone. In addition to the hypothalamic component of PRL regulation, there is a well-defined population of VIP cells within the pituitary, representing the only known example of VIP expression outside of nerve cells. This population of VIP cells is exquisitely responsive to thyroid status, and in common with the thyrotrope cell, is activated by hypothyroidism. Since VIP secretion is enhanced in the hypothyroid pituitary, and VIP release is stimulated by TRH, it is reasonable to postulate that paracrine VIP secretion may play a role in the reasonable to postulate that paracrine VIP secretion may play a role in the hyperprolactinemia prolactinemia that occurs in the hypothyroid human, although this is clearly not the case for the rat in whom hyperprolactinemia was not demonstrable. The role of VIP/PHI in human pituitary disease is unknown. We have been unable to identify any tumors that contain immunoreactive material using tissues prepared by standard methods. It may be that the demonstration of VIP/PHI is more demanding and will require better techniques for staining. The role of tuberoinfundibular VIP hypersecretion remains to be established but the evidence for stress-induced PRL hypersecretion in man encourages us to believe that at least some cases may be due to excessive hypothalamic activity. Additional potential neuroendocrine actions of VIP are in the secretomotor control of the ovary and thyroid, and in the regulation of somatostatin secretion and synthesis. In dispersed cell cultures (but not in whole hypothalamic slices from adult animals), VIP stimulates somatostatin secretion and independently stimulates the formation of somatostatin mRNA, an effect that can be duplicated in mixed cultures by treatment with forskolin, a postreceptor cAMP stimulator. In work carried out by Montminy and colleagues, the cAMP action has shown to be mediated by formation of a soluble protein that appears to activate the somatostatin gene promotor through interaction with a specific gene sequence.