The genomic era has fueled a rapid emergence of new information at the molecular level with a great potential for developing innovative approaches to detection, risk assessment, and management of oral cancers and premalignant disease. As yet, however, little research has been done on complementary approaches that would use different technology in conjunction with molecular approaches to create a rapid and cost-effective strategy for patient assessment and management. In our ongoing 8-year longitudinal study, a set of innovative technologies is being validated alone and in combination to best correlate with patient outcome. The plan is to use these devices in a step-by-step sequence to guide key clinicopathological decisions on patient risk and treatment. The devices include a hand-held visualization device that makes use of tissue autofluorescence to detect and delineate abnormal lesions and fields requiring follow-up, to be used in conjunction with optical contrast agents such as toluidine blue. In addition, two semi-automated high-resolution computer microscopy systems will be used to quantitate the protein expression phenotype of cell nuclei in tissue sections and exfoliated cell brushings. Previously identified risk-associated molecular changes are being used to validate these systems as well as to establish their place in a population-based triage program that will filter out high-risk cases in the community and funnel them to dysplasia clinics where higher-cost molecular tools will guide intervention. A critical development for the translation of this technology into community settings is the establishment of an effective methodology for education and training of health practitioners on the front lines.