Technological advances in DNA sequencing have provided unprecedented insights into the composition of the oral microbiome in health and disease, and RNA-sequencing and metabolomics-related technologies are beginning to yield information on the activities of these organisms. Importantly, progress in this area has brought the scientific community closer to an understanding of what constitutes a health-associated microbiome and is supporting the notion that the microbiota in healthy sites assumes an active role in promoting health and suppressing the acquisition, persistence, and activities of overt and opportunistic pathogens. It is also becoming clear that a significant impediment to developing a conclusive body of evidence that defines a healthy microbiome and the mechanisms by which beneficial bacteria promote health is that an inherent characteristic of the most abundant members of the oral flora, those that potentially play the greatest roles in health and disease, is intraspecies genomic diversity. In particular, individual isolates of abundant commensal and pathogenic streptococci show tremendous variability in gene content, and this variability manifests in tremendous phenotypic heterogeneity. Analysis of the consequences of this diversity has been complicated by the exquisite sensitivity these bacteria have evolved to environmental inputs, inducing rapid and substantial fluctuations in behaviors, and often only within subpopulations of the organisms. Thus, the conditions under which the oral microbiota is studied can produce widely different results within and between species. Fortunately, continually diminishing costs and ongoing refinements in sequencing and metabolomics are making it practical to study the oral microbiome at a level that will create a sufficiently robust understanding of the functions of individual organisms and reveal the complex interrelationships of these microbes ("the known unknowns") in a way that researchers will be able to engage in the rational design of reliable and economical risk assessments and preventive therapies.