The microbiome has recently joined the club of endocrine entities of the human body that are involved in homeostasis and disease. Microbiome characterizations are now typically included in longitudinal and cross-sectional population studies, associations with microbiome features have been made for almost any human disease, and the molecules by which the microbiome functionally contributes to host physiology are being elucidated. The leverage of these efforts for human health, however, is still rather modest. In this Perspective, we summarize some of the challenges that need to be overcome in order to make microbiome studies as informative for human health as genetic studies. Focusing on the role of the microbiome in host metabolism and inflammation, we also outline potential strategies that can be employed to achieve the next milestones in the journey toward microbiome-informed human health assessment and action.