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Diagnosing and treating lesions of the mouth and gums is challenging for most clinicians because of the wide variety of disease processes that can present with similar appearing lesions and the fact that most clinicians receive inadequate training in mouth diseases. Oral cancer, a common lesion in oral cavity, is not correctly diagnosing a clinical picture of an early squamous cell carcinoma. The prevalence of oral cancer continues to rise worldwide, related to the increase in consumption of tobacco, alcohol and other carcinogenic products. However, there has also been a significant reduction in mortality due to increasing awareness, early diagnosis and advances in treatments. This chapter is an attempt to provide a comprehensive update encompassing the spectrum of etiologic/risk factors, current clinical diagnostic tools, management philosophies, and molecular biomarkers and progression indicators of oral cancer.