Prostaglandins (PGs) are ubiquitous lipid mediators derived from cyclooxygenase metabolism of arachidonic acid that exert a broad range of physiologic activities, including modulation of inflammation, ovulation 1, 2 and arterial blood pressure 3, 4. PGE 2, a chief cyclooxygenase product, modulates blood pressure and fertility, although the specific G protein–coupled receptors 5, 6 mediating these effects remain poorly defined. To evaluate the physiologic role of the PGE 2 EP 2 receptor subtype, we created mice with targeted disruption of this gene (EP 2–/–). EP 2–/–mice develop normally but produce small litters and have slightly elevated baseline systolic blood pressure. In EP 2–/–mice, the characteristic hypotensive effect of intravenous PGE 2 infusion was absent; PGE 2 infusion instead produced hypertension. When fed a diet high in salt, the EP 2–/–mice developed profound systolic hypertension, whereas wild–type mice showed no change in systolic blood pressure. Analysis of wild–type and EP 2–/–mice on day 5 of pregnancy indicated that the reduced litter size of EP 2–/–mice is due to a pre–implantation defect. This reduction of implanted embryos could be accounted for by impaired ovulation and dramatic reductions in fertilization observed on day 2 of pregnancy. These data demonstrate that the EP 2 receptor mediates arterial dilatation, salt–sensitive hypertension, and also plays an essential part in female fertility.