The oral microbiome, a dynamic and polymicrobial community, plays a crucial role in the development of diseases such as dental caries and periodontitis. These diseases are driven by a feedforward loop between the microbiota and host factors, leading to dysbiosis and disease progression. The oral cavity harbors diverse microorganisms that colonize distinct microenvironments, such as teeth and mucosal membranes, each with unique microbial communities. These communities are regulated by sophisticated signaling systems and influenced by host and environmental factors. Periodontitis and dental caries are characterized by the emergence and persistence of dysbiosis, driven by inflammation and dietary sugars, respectively. The review discusses the mechanisms governing oral polymicrobial synergy and dysbiosis, highlighting the importance of interspecies interactions, extracellular matrix, and host immune responses. It also explores innovative therapeutic approaches to target these complex biological traits and protected oral niches, including multitargeted strategies for caries prevention and host modulation for periodontitis treatment. The authors emphasize the need for further research to identify additional disease-related microorganisms and their interactions, as well as the development of precise and effective therapeutic approaches.The oral microbiome, a dynamic and polymicrobial community, plays a crucial role in the development of diseases such as dental caries and periodontitis. These diseases are driven by a feedforward loop between the microbiota and host factors, leading to dysbiosis and disease progression. The oral cavity harbors diverse microorganisms that colonize distinct microenvironments, such as teeth and mucosal membranes, each with unique microbial communities. These communities are regulated by sophisticated signaling systems and influenced by host and environmental factors. Periodontitis and dental caries are characterized by the emergence and persistence of dysbiosis, driven by inflammation and dietary sugars, respectively. The review discusses the mechanisms governing oral polymicrobial synergy and dysbiosis, highlighting the importance of interspecies interactions, extracellular matrix, and host immune responses. It also explores innovative therapeutic approaches to target these complex biological traits and protected oral niches, including multitargeted strategies for caries prevention and host modulation for periodontitis treatment. The authors emphasize the need for further research to identify additional disease-related microorganisms and their interactions, as well as the development of precise and effective therapeutic approaches.