Oral health and systems medicine are intimately related but have remained, sadly, as isolated knowledge communities for decades. Are there veritable connector knowledge domains that can usefully link them together on the critical path to biomarker research and "one health"? In this context, it is noteworthy that bacteria form surface-attached communities on most biological surfaces, including the oral cavity. Biofilm-forming bacteria contribute to periodontal diseases and recent evidences point to roles of these bacteria in systemic diseases as well, with cardiovascular diseases, obesity, and cancer as notable examples. Interestingly, the combined mass of microorganisms such as bacteria are so large that when we combine all plants and animals on earth, the total biomass of bacteria is still bigger. They literally do colonize everywhere, not only soil and water but our skin, digestive tract, and even oral cavity are colonized by bacteria. Hence efforts to delineate biofilm formation mechanisms of oral bacteria and microorganisms and the development of small molecules to inhibit biofilm formation in the oral cavity is very timely for both diagnostics and therapeutics. Research on biofilms can benefit both oral and systems medicine. Here, we examine, review, and synthesize new knowledge on the current understanding of oral biofilm formation, the small molecule targets that can inhibit biofilm formation in the mouth. We suggest new directions for both oral and systems medicine, using various omics technologies such as SILAC and RNAseq, that could yield deeper insights, biomarkers, and molecular targets to design small molecules that selectively aim at eradication of pathogenic oral bacteria. Ultimately, devising new ways to control and eradicate bacteria in biofilms will open up novel diagnostic and therapeutic avenues for oral and systemic diseases alike.