Oral squamous cell carcinoma is a major cause of morbidity and mortality worldwide. Current experimental evidence shows that most important risk factors for oral cancer include tobacco use and excessive alcohol consumption and less well-defined risks include viral infection and a diet deficient in antioxidants. The positive correlation between various risk/etiologic factors of oral cancer and the activation of various transcription factors (TFs) has been reported in the literature. Although initially, TFs were considered to be very difficult targets for use in clinical treatment, recent technological advances have provided the ability to control these factors of cancer progression. This review focuses on the role of oncogenic transcription factors in oral cancer, their modes of activation through various biological pathways, the promises and pitfalls in viewing them as potent oncotargets, the way they can be controlled based on the current understanding, and the future research to be done in this area.