The MDR1 gene product P-glycoprotein is an ATP-dependent efflux pump, which transports its substrates out of cells. It is not only expressed in tumor cells, but also in cells of normal tissues. For example, it is located in the apical membrane of enterocytes, in endothelial cells forming the blood-brain and blood-testis barriers and in the apical membrane of placental syncytiotrophoblast. Since P-glycoprotein transports a wide range of drugs (e.g. antidepressants, antiepileptics, HIV protease inhibitors, cyclosporine, digoxin), its location in these tissues limits bioavailability of orally administered drugs and prevents entry of xenobiotics into the brain, testis and the fetus. Recent data highlight the role of intestinal P-glycoprotein for drug interactions (e.g. digoxin), of P-glycoprotein expressed in the blood-brain barrier for drug penetration into the CNS (e.g. loperamide, amitriptyline), the role of pharmacological inhibition of P-glycoprotein function to increases drug concentrations in sanctuary sites (e.g. for the HI virus) and for the potential role of MDR1 polymorphisms for P-glycoprotein expression, drug disposition, adverse drug reactions and disease risk. Taken together, active drug transport is now considered as an important additional mechanism limiting drug accumulation in multiple tissues including the CNS.