P-glycoprotein (Pgp), which is coded by human MDR1 (multidrug resistance) gene, is an energy-dependent efflux pump that exports its substrates out of the cell. Human Pgp is present not only in tumor cells but also in normal tissues including the kidney, liver, small and large intestine, brain, testis, and adrenal gland, and the pregnant uterus. This tissue distribution indicates that Pgp plays a significant role in excreting xenobiotics and metabolites into urine and bile and into the intestinal lumen, and in preventing their accumulation in the brain. The roles of Pgp in drug disposition include a urinary excretion mechanism in the kidney, a biliary excretion mechanism in the liver, an absorption barrier and determinant of oral bioavailability, and the blood–brain barrier that limits the accumulation of drugs in the brain. The inhibition of the transporting function of Pgp can cause clinically significant drug interactions and can also increase the penetration of drugs into the brain and the accumulation of drugs in the brain. Digoxin is a typical substrate for Pgp, which regulates the renal tubular secretion and brain distribution of digoxin. At present, potent Pgp inhibitors are being investigated in clinical trials aimed at overcoming the intrinsic or acquired multidrug resistance of human cancers. The clinical application of these Pgp inhibitors should take into consideration the physiologic function of pgp.