Use of microbiome-based biomarkers in diagnosis, prognosis, risk profiling, and precision therapy requires definition of a healthy microbiome in different populations. To determine features of the intestinal microbiota associated with health, however, we need improved microbiome profiling technologies, with strain-level resolution. We must also learn more about how the microbiome varies among apparently healthy people, how it changes with age, and the effects of diet, medications, ethnicity, geography, and lifestyle. Furthermore, many intestinal microbes, including viruses, phage, fungi, and archaea, have not been characterized, and little is known about their contributions to health and disease.Whether a healthy microbiome can be defined is an important and seemingly simple question, but with a complex answer in continual need of refinement.