When certain coadministered drugs interfere with the transport of one another at the P-glycoprotein (Pgp) level, we observe the phenomenon of "drug-drug interactions". We describe here the physical and biochemical ways that drugs react with Pgp, the induction of Pgp by xenobiotics and the polymorphisms of Pgp related to drug-drug interactions. We also describe methods that can be used to detect potential drug-drug interactions. Among the widely used methods are flow cytometry, cell culture with polarized expression of Pgp, liposome and inside-out membrane preparations, ex vivo studies, in silico calculations, cDNA microarrays, in vivo mouse models, positron emission tomography (PET), and nuclear magnetic resonance (NMR) methods with live animals.