Grapefruit juice produces mechanism-based inhibition of intestinal drug metabolism when consumed in normal quantities. This can produce clinically important increases in oral drug bioavailability when coadministered with substrates of cytochrome P450 3A4 (CYP3A4) that undergo high presystemic metabolism. Furanocoumarins such as bergamottin and 6′,7′-dihydroxybergamottin have been identified as probable active constituents. Grapefruit juice may also inhibit intestinal P-glycoprotein-mediated efflux transport of drugs such as cyclosporine to increase its oral bioavailability. However, grapefruit juice does not enhance the absorption of digoxin, a prototypical P-glycoprotein substrate, likely because it has high inherent oral bioavailability. Grapefruit and other fruit juices have recently been shown to be potent in vitro inhibitors of a number of organic anion-transporting polypeptides (OATPs). These juices were also found to decrease the absorption of the nonmetabolized OATP substrate, fexofenadine. Taken together, the data support inhibition of intestinal uptake transporters by fruit juices to decrease drug bioavailability. This would represent a new mechanism for food–drug interactions. These findings with grapefruit and other fruit juices continue to enhance our understanding of the complex nature of food–drug interactions, and their possible influence on the clinical effects of medications.