Both metabolizing enzymes and drug transporters play important roles in modulating drug absorption, distribution, metabolism and elimination. Acting alone or in concert with each other they can affect the pharmacokinetics and pharmacodynamics of a drug. This paper will present cases from recent reviews of new drug application (NDA) and literature that exemplify the role of metabolizing enzyme-transporter interplay in a drug's disposition, and discuss challenges in predicting drug interactions. Finally, the discussion will focus on the need to leverage current knowledge to obtain more meaningful drug interaction information.