The biological actions of prostaglandin (PG) D(2) include vasodilatation, bronchoconstriction, inhibition of platelet aggregation, and recruitment of inflammatory cells. Characterization of DP receptor null mice in which antigen-induced airway and inflammatory responses are attenuated and identification of CRTH2 as a novel PGD(2) receptor have shed light on the role of PGD(2) in the immune and inflammatory responses. Hematopoietic PGD synthase (H-PGDS) is a cytosolic enzyme that isomerizes PGH(2), a common precursor for all PGs and thromboxanes, to PGD(2) in a glutathione-dependent manner. H-PGDS is expressed in mast cells, antigen-presenting cells, and Th2 cells, and is the only mammalian member of the Sigma class of cytosolic glutathione S-transferases. In this review, we focus on the molecular biology of H-PGDS, the determination of its three-dimensional structure, characterization of the regulation of its gene expression, and information gleaned from transgenic animals.