Cytochrome P450 3A4 (CYP3A4), the major phase I drug metabolizing enzyme in humans, and the MDR1 gene product P‐glycoprotein (P‐gp) are present at high concentrations in villus tip enterocytes of the small intestine and share a significant overlap in substrate specificity. A large body of research both in vitro and in vivo has established metabolism by intestinal CYP3A4 as a major determinant of the systemic bioavailability of orally administered drugs. More recently it has been recognized that drug extrusion by intestinal P‐gp can both reduce drug absorption and modulate the effects of inhibitors and inducers of CYP3A‐mediated metabolism. There is relatively little data regarding the effects of CYP3A and P‐gp on peptide drugs; however, studies with the cyclic peptide immunosuppresant cyclosporine as well as peptidomimetics such as the HIV‐protease inhibitor saquinavir (Invirase) and a new cysteine protease inhibitor K02 (Morpholine‐Urea‐Phe‐Hphe‐Vinyl sulfone; Axys Pharmaceuticals) provide some insight into the impact of these systems on the oral absorption of peptides.