P-glycoprotein (P-gp), encoded by the MDR1 (ABCB1) gene, is a major efflux transporter that significantly affects the tissue distribution of a large number of drugs and therefore their efficacy and toxicity. Genetic and chemical knock-out studies in rodents indicate that the greatest impact of P-gp on tissue distribution of drugs is at the blood-brain barrier (BBB) and the blood-placenta barrier (BPB). If true, one strategy to increase the CNS and fetal delivery of drugs is to chemically inhibit P-glycoprotein. Prior to pursuing this strategy, a few key questions need to be addressed. First, is P-gp at the human BBB and BPB as importantin as that in rodents in preventing distribution of drugs into the brain and the fetus? Second, if it is, can it be significantly inhibited to increase the delivery of drugs to these previleged compartments? Studies in my laboratory and those of others have begun to address these questions in both humans (BBB) and non-human primates (BPB) by using the noninvasive state-of-the-art technique, positron emission tomography (PET). To do so, we have utilized 11C-verapamil as a prototypic P-gp substrate and cyclosporine A as the prototypic P-gp inhibitor. My presentation will review these studies.