The gut microbiota has been recognized as the ‘second genome’ and a new ‘metabolic organ’ to us humans and gut microbial shifts, including those both at the structural and functional levels, have been implicated in the pathogenesis and development of various metabolic disorders. Growing evidence suggests that those tiny microorganisms affect not only the precise diagnosis of common metabolic diseases but also the clinical effectiveness and efficacy of associated therapeutic options, especially that of medications and diets. Here in this review, we discussed the reciprocal interventions between gut microbes and those xenobiotics as well as their importance to the precise management of various metabolic disorders, the International Human Phenome Project, and personalized medicine.