Our understanding of the microbiome is advancing rapidly, and continues to productively move through the discovery phase, with numerous correlations being established between specific commensal microbes or microbiota compositions and a wide range of diseases that includes infections, inflammatory conditions, metabolic disease, autoimmunity and neurologic syndromes. The initial discovery of these potentially important correlations has led many laboratories around the world to probe the molecular mechanisms that form the causal link between specific commensal microbes and disease development, progression and resolution. Although there have been great advances, culturing many of the prevalent and metabolically active obligate anaerobic commensals remains a challenge. Exciting advances, however, are emerging from laboratories developing tools to genetically manipulate key commensal organisms, facilitating experimental studies that are identifying the small, bioactive molecules they produce, some of which have therapeutic potential. Studies of the impact of bacteriophage on the microbiota also suggest that they may have therapeutic potential. This Keystone conference will focus on recent advances that demonstrate, at the cellular and molecular level, the impact of the microbiota and its products on disease susceptibility/resistance, with an emphasis on microbial and host metabolism, inter-microbial interactions and the amelioration of diseases.