The gut microbiome harbors trillions of organisms that contribute to human health and disease. These bacteria can also affect the properties of medical drugs used to treat these diseases, and drugs, in turn, can reshape the microbiome. Research addressing interdependent microbiome-host-drug interactions thus has broad impact. In this Review, we discuss these interactions from the perspective of drug bioavailability, absorption, metabolism, excretion, toxicity, and drug-mediated microbiome modulation. We survey approaches that aim to uncover the mechanisms underlying these effects and opportunities to translate this knowledge into new strategies to improve the development, administration, and monitoring of medical drugs.