Head and neck cancer including oral squamous cell carcinoma (OSCC) is the sixth most common cancer in the world. OSCC has a high potential for local invasion and nodal metastasis, and the overall 5-year survival rate has not significantly changed during the past 30 years. Recent research has elucidated the detailed molecular mechanisms of carcinogenesis, tumor progression, and metastasis of OSCC. It is generally accepted that OSCC arises from multiple genetic alterations caused by chronic exposure to carcinogens such as alcohol, smoking, viral infections, and inflammation. The molecular mechanisms of carcinogenesis, tumor progression, and metastasis of head and neck cancer have been elucidated by recent advances in molecular biology. However, many unsolved questions remain. In this review, we describe the current molecular biological findings such as human papillomavirus infection, epithelial-mesenchymal transition, microRNA, and our novel molecular pathological findings of OSCC.