Prostaglandin (PG) D2 is a major PG produced in the central nervous system and is involved in the regulation of sleep and pain responses through DP receptors. It is also actively produced by mast cells, basophils, and Th2 cells, acting as an allergic mediator through DP and CRTH2 receptors. PGD2 is further dehydrated to produce PGJ2, delta12-PGJ2, and 15-deoxy-delta(12,14)-PGJ2, the last being a ligand for the nuclear receptor PPARgamma. PGD synthase (PGDS) catalyzes the isomerization of PGH2 to PGD2 in the presence of sulfhydryl compounds. Two distinct types of PGDS have been identified: one is the lipocalin-type PGDS (L-PGDS); and the other, the hematopoietic PGDS (H-PGDS). We isolated the human and mouse cDNAs and genes for L-PGDS and H-PGDS, determined their X-ray crystallographic structures, examined their tissue distribution profiles and cellular localization, and generated gene-knockout mice and human enzyme-overexpressing transgenic mice. L-PGDS and H-PGDS are quite different from each other, in terms of their amino acid sequence, tertiary structure, evolutional origin, chromosomal and cellular localization, tissue distribution, and also functional relevance. Therefore, L-PGDS and H-PGDS are considered to be a novel example of functional convergence.