Molecular factors from the gut microbiota provide the host with the right metabolic, immunological, and neurological components to support health and well-being. However, certain circumstances can rupture the mutualistic pact with our intestinal counterpart, pushing the gut microbiome toward a dysbiotic layout, where microbiome-derived molecules may contribute to a disease state. We are now beginning to understand the microbiota-host co-regulated pathways underlying these processes, paving the way for a new era of rational piloting of the gut microbiome functions, through the design of a new generation of microbiome-targeting drugs. Microbiota-derived metabolites are emerging as promising starting hit compounds to modulate human targets, hence triggering certain pharmacological responses. In conclusion, drug discovery targeting the gut microbiota as well as the characterization of microbiota-derived metabolites can represent innovative medicinal chemistry possibilities toward the identification of novel drug candidates, targets, and more in general innovative ways for the treatment of unmet medical needs.