Improving children’s oral health is a long-standing area of priority and sustained efforts by many stakeholders. Despite these efforts, dental caries, particularly early childhood caries (ECC), persists as a clinical and dental public health problem with multilevel consequences. Despite recent successes in the non-restorative management of dental caries, remarkably little has been done in the domain of ECC prevention. There is promise and expectation that meaningful improvements in early childhood oral health and ECC prevention can be made via the advent of precision medicine in the oral health domain. We posit that precision dentistry, including genomic influences, may be best examined in the context of well-characterized communities (versus convenience clinical samples) and the impact of contextual factors including geography and social disadvantage may be explainable via mechanistic (i.e., biological) research. This notion is aligned with the population approach in precision medicine, which calls for the latter to be predictive, preventive, personalized, and participatory. The article highlights research directions that must be developed for precision dentistry and precision dental public health to be realized. In this context, we describe the rationale, activities, and early insights gained from the ZOE 2.0 study – a large-scale, community-based, genetic epidemiologic study of early childhood oral health. We anticipate that this long-term research program will illuminate foundational domains for the advancement of precision dentistry and precision dental public health. Ultimately, this new knowledge can help catalyze the development of effective preventive and therapeutic modalities via actions at the policy, community, family, and person level.