The gut microbiota has emerged as an important drug target due to its substantial effects on host health and capacity to alter the physiochemistry of numerous chemicals. Bidirectional interactions between drugs and the microbiota directly and indirectly affect host metabolism and homeostasis. Several drugs induce gastrointestinal toxicities by perturbing gut microbiota composition, allowing colonization of pathogens and disturbing the synergy between the microorganisms and their hosts. In return, microorganisms metabolize drugs to gain energy and nutrients. These biotransformation reactions affect the disposition of drugs in the body and modulate their efficacy and toxicity. Microorganisms can indirectly contribute to drug pharmokinetics in the body via microbial products regulating host gene expression. Recent developments in in vivo, in vitro, and in silico approaches coupled with multi-omics are advancing our understanding of these complex interactions. Ultimately, integrating an understanding of microbiome–drug interactions to personalized medicine will lead to safer, more economical, and more effective therapies.