Squamous cell carcinoma of the oral cavity (OCSCC) is the most frequently observed form of head-and-neck cancer in Southeast Asia and is the sixth most common cancer worldwide. Most cases of this preventable disease are caused by alcohol consumption, smoking and betel nut chewing. The survival rates of patients with advanced OCSCC have not increased significantly in recent years. While treatments for OCSCC are similar worldwide, survival rates differ by geographical area. The various genetic profiles and individual genetic susceptibility for carcinogens may account for this discrepancy. In some respects, molecular alteration or accumulation affects tumor progression and the clinical outcomes among patients with OCSCC. Clarifying the tumor behavior of oral cancer, with regard to pathological features or molecular aspects, could help clinicians to judge, tailor and adopt more effective therapeutic strategies to treat oral cancer.