Approximately 95% of malignant neoplasms of the oral and oropharyngeal region are represented by the histologic diagnosis of squamous cell carcinoma (SCC), with the remainder largely consisting of salivary gland neoplasms. Epithelial carcinogenesis is thought to be a multistep process involving the sequential activation of oncogenes and the inactivation of tumor suppressor genes in a clonal population of cells. These genetic and epigenetic changes generate concomitant phenotypic changes in the tumor cells that promote their survival and proliferation (1). A number of reproducible molecular alterations, some definitively characterized and some inferred, have been identified in both oral potentially malignant disorders (OPMDs) and SCC. This chapter will summarize the currently available data with respect to the molecular changes observed in OPMDs and SCC. Importantly, rather than merely providing a list of individual genetic alterations observed with some varying incidence/prevalence within small cohorts of patients, this chapter will instead focus on studies that have investigated entire classes of genetic changes at a global level. Where possible, it will also seek to correlate these molecular changes with potential improvements in the areas of diagnosis, prognosis and prediction.