The human gut microbiome harbors hundreds of bacterial species with diverse biochemical capabilities. Dozens of drugs have been shown to be metabolized by single isolates from the gut microbiome, but the extent of this phenomenon is rarely explored in the context of microbial communities. Here, we develop a quantitative experimental framework for mapping the ability of the human gut microbiome to metabolize small molecule drugs: Microbiome-Derived Metabolism (MDM)-Screen. Included are a batch culturing system for sustained growth of subject-specific gut microbial communities, an ex vivo drug metabolism screen, and targeted and untargeted functional metagenomic screens to identify microbiome-encoded genes responsible for specific metabolic events. Our framework identifies novel drug-microbiome interactions that vary between individuals and demonstrates how the gut microbiome might be used in drug development and personalized medicine. Display omitted •Development of subject-personalized ex vivo batch cultures of the gut microbiome•Discovery of diverse drug-microbiome interactions using MDM-Screen•MDM-Screen quantifies drug metabolism by personalized gut microbial communities•Functional genomic and metagenomic screens identify drug-metabolizing enzymes Each human has a diverse gut microbiome, which can metabolize drugs differently. In this resource, Javdan et al. present a way to capture and grow much of the unique diversity of human microbiomes in culture and also a way to detect many of our microbiome-derived metabolites. Together, they use these unique gut communities and the metabolomics pipeline to see how personalized microbiomes metabolize drugs in different ways.