The trillions of bacteria that constitutively colonize our intestines (our gut microbiota) produce tens of thousands of small molecule metabolites that can potentially affect nearly all aspects of human physiology. However, the biological functions of the vast majority of these metabolites remain undiscovered. We are pursuing an orthogonal approach to this problem, where we use host sensing of microbiota metabolites by defined receptors as a lens to illuminate the ‘dark matter’ of the bioactive microbiota metabolome. We believe that this approach will eventually enable us to mine the full depths of the bioactive microbiota metabolome.