Prostanoids are a series of bioactive lipid metabolites that function in an autacoid manner via activation of cognate GPCRs. Nonsteroidal anti-inflammatory drugs such as aspirin work by inhibiting COX enzymes. PGE₂ acts on four receptor subtypes, EP1–EP4, and has the most versatile functions among the prostanoids. Prostaglandin E receptor EP4 is involved in disorders such as cancer and autoimmune disease. We have revealed the crystal structure of human EP4 in complex with its antagonist ONO-AE3-208 and an inhibitory antibody at 3.2 Å resolution (Nat. Chem. Biol. 2019). The structure showed that the extracellular surface is occluded by the extracellular loops and that the antagonist lies at the interface with the lipid bilayer, proximal to the highly conserved Arg316 residue in the seventh transmembrane domain. This structural information also provides insight into the ligand entry pathway from the membrane bilayer to the EP4 binding pocket. EP3 is involved in generation of fever, contraction of smooth muscles, thrombosis, and angiogenesis. We have determined the crystal structure of human prostaglandin E receptor subtype EP3 bound to endogenous ligand PGE₂ at 2.9 Å resolution (Nat. Chem. Biol. 2019). The structure revealed important insights into the activation mechanism of prostanoid receptors and provides a molecular basis for the binding modes of endogenous ligands. We have determined the cryoelectron microscopy (cryo-EM) structure of the EP4-heterotrimeric G protein (Gs) complex with the endogenous ligand at 3.3 Å resolution (Structure 2021). In this structure, compared with that in the inactive EP4 structure, the sixth transmembrane domain is shifted outward on the intracellular side, although the shift is smaller than that in other class A GPCRs bound to Gs.