Most progressive and severe acute kidney diseases lead to renal fibrosis, for which we still lack effective treatment options. Prostaglandin E2 (PGE2) is one of the most abundant prostanoids, exerting its pleiotropic functions via four receptors, EP1 through EP4. Recent studies indicate that the PGE2-EP4 pathway is a potent endogenous renoprotective system that limits renal fibrosis by acting on multiple cellular targets.