Metabolites have emerged as the quintessential effectors mediating the impact of the commensal microbiome on human physiology, both locally at the sites of microbial colonization and systemically. The endocrine activity of the microbiome and its involvement in a multitude of complex diseases has made microbiome-modulated metabolites an attractive target for the development of new therapies. Several properties make metabolites uniquely suited for interventional strategies: natural occurrence in a broad range of concentrations, functional pleiotropy, ease of administration, and tissue bioavailability. Here, we provide an overview of recently discovered physiological effects of microbiome-associated small molecules that may serve as the first examples of metabolite-based therapies. We also highlight challenges and obstacles that the field needs to overcome on the path toward successful clinical trials of microbial metabolites for human disease.