P-glycoprotein (ABCB1) is one of the most extensively studied transporters regarding drug resistance and drug-drug interactions. P-glycoprotein is expressed in multiple key organs in drug disposition such as small intestine, blood-brain barrier, kidney, and liver. Therefore, P-glycoprotein mediated drug-drug interactions can occur at various organs and tissues. This chapter will mainly focus on drug-drug interactions that are mediated by the intestinal P-glycoprotein.During the last decade, many in vitro and in vivo studies reported that the induction or inhibition of P-glycoprotein can lead to drug-drug interactions. For instance, induction of the intestinal P-glycoprotein activity can cause reduced bioavailability of orally administered drugs and decreased therapeutic efficacy. On the other hand, the inhibition of the intestinal P-glycoprotein activity can lead to increased bioavailability, thus leading to an increased risk of adverse side effects.