Intestinal phase I metabolism and active extrusion of absorbed drug have recently been recognised as major determinants of oral bioavailability. Cytochrome P450 (CYP) 3A, the major phase I drug metabolising enzyme in humans, and the multidrug efflux pump, P-glycoprotein, are present at high levels in the villus tip of enterocytes in the gastrointestinal tract, the primary site of absorption for orally administered drugs. The importance of CYP3A and P-glycoprotein in limiting oral drug delivery is suggested to us by their joint presence in small intestinal enterocytes, by the significant overlap in their substrate specificities, and by the poor oral bioavailability of joint substrates for these 2 proteins. These proteins are induced or inhibited by many of the same compounds. A growing number of preclinical and clinical studies have demonstrated that the oral bioavailability of many CYP3A and/or P-glycoprotein substrate drugs can be increased by concomitant administration of CYP3A inhibitors and/or P-glycoprotein inhibitors. We believe that further understanding the physiology and biochemistry of the interactive nature of intestinal CYP3A and P-glycoprotein will be important in defining, controlling, and improving oral bioavailability of CYP3A/P-glycoprotein substrates.