Endogenous prostaglandin (PG) E2 production potently modulates salt and water transport in the kidney. Multiple direct effects of PGE2 on epithelial water and sodium transport have been demonstrated in the rabbit cortical collecting duct (CCD). Both functional and molecular studies now suggest that these disparate effects of PGE2 on CCD function are mediated by different EP receptors. When added in the presence of vasopressin, PGE2 inhibits cyclic AMP generation and water absorption. These effects are mediated via an inhibitory G-protein (Gi). In situ hybridization demonstrates high levels of expression of the Gi-coupled EP3 receptor in the rabbit collecting duct. However, by itself, PGE2 also stimulates cyclic AMP generation and water permeability. These effects appear to be mediated via a distinct EP receptor (possibly an EP4 receptor). PGE2 also increases intracellular Ca2+ in the CCD and inhibits Na+ absorption via a Ca(2+)-dependent mechanism. The EP1 receptor is postulated to be responsible for this action of PGE2. We suggest receptor-selective prostaglandin analogs may be used to selectively modulate sodium and water transport in the kidney.