Associations between the dynamic community of microbes (the microbiota) and the host they colonize appear to be vital for ensuring host health. Microbe-host communication is actively maintained across physiological barriers of various body sites and is mediated by a range of bidirectional secreted proteins and small molecules. So far, a range of "omics" methods have succeeded in revealing the multiplicity of associations between members of a microbiota and a wide range of host processes and diseases. Although these advances point to possibilities for treating disease, there has not been much translational success thus far. We know little about which organisms are key contributors to host health, the importance of strain differences, and the activities of much of the chemical "soup" that is produced by the microbiota. Adding to this complexity are emerging hints of the role of interkingdom interactions between bacteria, phages, protozoa, and/or fungi in regulating the microbiota-host interactions. Functional approaches, although experimentally challenging, could be the next step to unlocking the power of the microbiota.