In the era of applied meta-omics and personalized medicine, the oral microbiome is a valuable asset. From biomarker discovery to being a powerful source of therapeutic targets, and to presenting an opportunity for developing non-invasive approaches to health care, it has become clear that oral microbes may hold the answer for understanding disease, even beyond the oral cavity. Although our understanding of oral microbiome diversity has come a long way in the past 50 years, there are still many areas that need to be fine-tuned for better risk assessment and diagnosis, especially in early developmental stages of human life. Here, we discuss the factors that impact development of the oral microbiome, and explore oral markers of disease, with a focus on the early oral cavity. Our ultimate goal is to put different experimental and methodological views into perspective for better assessment of early oral and systemic disease at an early age, and discuss how oral microbiomes- at the community level, could provide improved assessment in individuals, and populations at risk.