Prostaglandin (PG) E2 and PGD2, which are biosynthesized from arachidonic acid generated by enzymatic cleavage of membrane phospholipid in response to various stimuli, play key roles in multiple brain pathophysiological processes, including modulation of synaptic plasticity, neuroinflammation, and sleep promotion. Concentrations of PGE2 and PGD2 in brain interstitial fluid (ISF) and cerebrospinal fluid (CSF) are maintained at appropriate levels for normal brain function by regulatory systems. The blood-brain barrier (BBB) and the blood-CSF barrier (BCSFB) possess ISF/CSF-to-blood efflux transport systems that are the primary cerebral clearance pathways for PGE2 and PGD2. However, regulatory dysfunction at the brain barriers may seriously affect brain function. In a mouse inflammation model, significant reduction of PGE2 efflux transport at the BBB has been observed. Several kinds of cephalosporin antibiotics and nonsteroidal anti-inflammatory drugs inhibit the BBB- and BCSFB-mediated efflux transport of PGE2 and PGD2. Especially, drugs that inhibit multidrug resistance-associated protein 4 (MRP4)-mediated PGE2 transport are capable of reducing PGE2 efflux at the BBB. Thus, it might be important in the treatment of inflammatory and infectious diseases to use drugs that do not inhibit clearance of PGE2 at the brain barriers, in order to avoid unexpected adverse CNS effects. Further, considering that PGD2 in CSF is a natural sleep-promoting factor, changes in the activity of the PGD2 efflux transport system at the BCSFB may modify the PGD2 level in CSF, thus affecting physiological sleep. These findings indicate that the efflux transport systems at the brain barriers play key roles in the pathophysiology and pharmacology of PGE2 and PGD2.