This chapter describes the recent progress on the molecular mechanism of prostaglandin (PG) D2-induced sleep, basic and clinical studies on the roles of PGD2 in physiological sleep regulation, and current and emerging roles of adenosine in regulating sleep. There are two distinct types of PGD synthase (PGDS), one being lipocalin-type PGDS (L-PGDS) and the other, hematopoietic PGDS (H-PGDS). When PGD2 is infused into the subarachnoid space of the basal forebrain of wild-type mice, the region in which DP1 receptors are most abundant, the extracellular adenosine concentration increases in a dose-dependent manner. This increase is absent in DP1 receptor knockout (KO) mice, indicating that the increase in adenosine in the subarachnoid space depends on DP1 receptors. Adenosine deaminase, an enzyme that catabolizes adenosine to inosine, is predominantly localized in the tuberomammilary nucleus (TMN) of the brain.