Breast cancer resistance protein (BCRP/ABCG2), an ATP-binding cassette (ABC) membrane-associated drug efflux transporter, is known to localize at the blood-brain barrier (BBB) and can significantly restrict xenobiotic permeability in the brain. The objective of this study is to investigate the regulation of BCRP functional expression by peroxisome proliferator-activated receptor alpha (PPAR␣), a ligand-activated transcription factor primarily involved in lipid metabolism, in a cerebral microvascular endothelial cell culture system (hCMEC/D3), representative of human BBB. We demonstrate that PPAR␣-selective ligands (i.e., clofibrate, GW7647) significantly induce BCRP mRNA and protein expression in a time-and concentrationdependent manner, whereas pharmacological inhibitors (i.e., MK886, GW6471) prevent this induction.