Therapy with two or more drugs is more the rule than the exception, particularly in aging societies. Drug-drug interactions are frequently undesirable and may lead to increased toxicity and mortality. Inhibition of transporters is one major mechanism underlying drug-drug interactions. The myriad of potential drug combinations makes it very challenging to predict drug-drug interactions. This Commentary discusses potential advantages and limitations of endogenous compounds for predicting transporter-mediated drug-drug interactions.