In ruminants, the corpus luteum (CL) of early pregnancy is resistant to luteolysis. Prostaglandin (PG)E-2 is considered a luteoprotective mediator. Early studies indicate that during maternal recognition of pregnancy (MRP) in ruminants, a factor(s) from the conceptus or gravid uterus readies the ovary locally through the utero-ovarian plexus (UOP) and protects the CL from luteolysis. The local nature of the embryonic antiluteolytic or luteoprotective effect precludes any direct effect of a protein transported or acting between the gravid uterus and CL in ruminants. During MRP, interferon tau (IFNT) secreted by the trophoblast of the conceptus inhibits endometrial pulsatile release of PGF(2 alpha) and increases endometrial PGE(2). Our recent studies indicate that (1) luteal PG biosynthesis is selectively directed toward PGF(2 alpha), at the time of luteolysis and toward PGE(2) at the time of establishment of pregnancy (ESP); (2) the ability of the CL of early pregnancy to resist luteolysis is likely due to increased intraluteal biosynthesis and signaling of PGE(2); arid (3) endometrial PGE, is transported from the uterus to the CL through the FOP vascular route during ESP in sheep. Intrauterine co-administration of IFNT and prostaglandin E-2 synthase 1 (PGES-1) inhibitor reestablishes endometrial PGF(2 alpha), pulses and regresses the CL. In contrast, intrauterine co-administration of IFNT and PGES-1 inhibitor along with intraovarian administration of PGE, rescues the CL. Together, the accumulating information provides compelling evidence that PGE(2) produced by the CL in response to endometrial PGE(2) induced by pregnancy may counteract the luteolytic effect of PGF(2 alpha), as an additional luteoprotective mechanism during MRP or ESP in ruminants. Targeting PGE(2) biosynthesis and signaling selectively in the endometrium or CL may provide luteoprotective therapy to improve reproductive efficiency in ruminants.