The human oral cavity represents a complex ecology of approximately 500 microbial species existing as commensals, and interacting with human/host factors. Perturbation of this ecosystem can lead to diseases of the oral cavity. The oral cavity also acts as a mirror of complex systemic diseases. Unique challenges and opportunities in oral healthcare exist in the diagnosis and treatment of primary disorders of the oral cavity or manifestations of systemic diseases. The completion of human and microbial genome projects has provided a wealth of information that will permit the application of pharmacogenomics - how genetic variations within the commensal and the host will impact the efficacy of drugs, and the diagnosis and treatment of oral disease. This review highlights opportunities focusing on oral health where pharmacogenomics can be applied.