Experimental approaches. Experimental approaches. Although we have been aware of isolated, but clinically relevant examples for a number of years, most commentators agree that the current bank of known pharmacomicrobiomic reactions is likely to be expanded greatly in future years. Coupled with clinical observations, a range of experimental approaches may be geared toward extracting complementary information about the complex and bidirectional interplay between the gut microbiome and xenobiotics. Many of the strategies employed, such as the use of germ-free models or those generated via depletion of the gut microbiota with a cocktail of antibiotics, can provide valuable pharmacokinetic and pharmacodynamic insights. Insights from invertebrate germ-free models, such as the nematode C. elegans, are increasingly used to inform our understanding of host–microbe interactions. More routine screening of reciprocal microbiome–xenobiotic interactions can be conducted in various in vitro batch culture or fermentation systems or in the more complex simulator of the human intestinal microbial ecosystem. Fecal sample incubations, such as fecalase or cecalase assays, are often used in xenobiotic metabolism studies. Functional metagenomics and bioinformatics can be used to guide rational, mechanistically-oriented microbiome-targeted therapeutic interventions. There is also a variety of predictive and computational tools for the evaluation of microbial effects on drugs during gastrointestinal passage that can be used to streamline the process and provide targets for downstream in vitro and in vivo hypothesis assessments. Organ-on-a-chip microphysiological systems are likely to increase efficiency and contribute in the future to a better understanding of microbial metabolism and host–microbiome crosstalk. Gastrointestinal organoids can be used to more accurately model aspects of epithelial barrier dynamics, including cellular differentiation and proliferation, in specific intestinal segments and bring advantages over cell culture models in unraveling the molecular basis of the host–microbe interactions. Gerard Clarke et al. Pharmacol Rev 2019;71:198-224 Copyright © 2019 The Author(s).