Efforts to define the physiological impacts of the human microbiome have led to several intriguing findings. First, thousands of small molecules of microbial origin are present in human blood or stool at micro- to millimolar concentrations. Second, phenomenological studies in animals have implicated some of these molecules in immune system development, behavioral phenotypes, and many additional processes. Third, variations in abundances of these molecules in humans are associated with autoimmune and neurological disorders, among others. Subsequent mechanistic investigations have revealed new biology, such as microbiome-derived small molecules that induce genotoxicity or impact atherosclerosis by binding adrenergic receptors on platelets. Together, these findings imply that microbiome-derived small molecules form the language of a cross-kingdom chemical dialogue that plays an important role in human biology. The main goal of our research is to define this dialogue from its chemical underpinnings to its physiological consequences. In my presentation, I will discuss our overarching goals, and how we tackle these goals using a combination of systematic phenotypic screens and high-throughput genetics, using examples from our ongoing work to illustrate both.