The retinal pigment epithelium (RPE) is a single cell layer juxtaposed between the neural retina and the choroid and functions as a blood-retina barrier. The RPE performs functions essential for photoreceptor (PR) survival. Although the regulation of these functions has remained unknown, it is a distinct possibility that the RPE is under constant regulation by signaling molecules coming from the choroid and the retina. Vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide present in the retina and in the choroid, has been shown to promote the growth and differentiation of a variety of cells in tissue and organ cultures. In cultured RPE cells, VIP is the one most effective stimulator of the cAMP signaling pathway among a long list of neurotransmitters and modulators tested. For example, VIP, at 1 microM, stimulates the intracellular cAMP to 80-100- and 20-fold in 3 min in RPE cells cultured from chick embryos and adult human donor eyes, respectively. In cultured chick embryonic RPE, VIP is also shown to be a potent and effective modulator of pp60(c-src), the non-receptor tyrosine kinase present in differentiating and terminally differentiated cells. VIP stimulates both overall phosphorylation at unknown sites and phosphotyrosine dephosphorylation in pp60(c-src). A 190-kDa microtubule-associated protein is known to be one of the downstream targets in VIP-modulated signaling pathways. At the cellular level, VIP stimulates cell proliferation modestly and melanogenesis pronouncedly in growing chick embryonic RPE cultures. Ultimately, the differentiation goal of RPE cells in vivo is to perform functions that are essential for photoreceptor survival. On bare permeable supports (that is, without biological material coating), the chick embryonic RPE cells grow to become RPE sheets with a cytoarchitecture that allows the display of two of the RPE functions. These cultures demonstrate structural polarity and are functionally polarized, allowing for proper macromolecule secretion and fluid transport. VIP is shown to stimulate macromolecule secretion at the apical surface (retina facing) and the development of the capacity for fluid transport from the apical to the basal surface of the RPE sheet. In conclusion, studies in our laboratory indicate that VIP is a differentiation promotor during the development of a functional RPE. Recent advances in the molecular biology of melanogenesis and the fluid transport-linked Na-K-2Cl cotransporter in other cells will allow future studies of VIP modulated events in the RPE at the molecular level. Finally, identification of RPE differentiation factors may prove essential for the ultimate success of RPE transplantation, thus promoting the rescue of photoreceptor cells in retinal degeneration.