Most drugs are taken orally. For those intended to act systemically, a significant fraction of the dose can be eliminated during its first passage through a sequence of organs before entry into the general circulation. For some drugs, the degree of first-pass elimination can be large enough such that oral bioavailability is significantly reduced, with the consequent potential for a reduced clinical response. Of these first-pass eliminating organs, the small intestine and liver are the most commonly implicated, in part because they express the highest levels of drug-metabolizing enzymes. For several drugs whose major route of elimination occurs via CYP3A-mediated metabolism, the extent of first-pass metabolism in the small intestine can rival that in the liver. As such, alterations in enteric CYP3A activity alone can significantly influence oral bioavailability. The most extensively studied xenobiotic shown to inhibit only enteric CYP3A is grapefruit juice, the consequences of which can be clinically significant. Although much information has been gained regarding the grapefruit juice effect, progress in the relatively understudied area of drug-diet interactions continues to be sluggish and reactive. In stark contrast, the potential for drug-drug interactions involving any new therapeutic agent must be evaluated, prospectively, before market introduction. To prospectively elucidate mechanisms underlying drug-diet interactions, a multidisciplinary, translational research approach is required, which capitalizes on the collective expertise of drug metabolism scientists and natural products chemists. Such an approach would allow proper between-study comparisons, and ultimately provide conclusive information as to whether specific dietary substances can be taken safely with certain medications.