Head and neck squamous cell carcinoma is a well-known model for chemoprevention studies because of its field cancerization effect, its multistep carcinogenesis process, and the easy accessibility of biopsies to target lesions. With new understandings of head and neck carcinogenesis and the development of molecular targeted therapy, chemoprevention trials for head and neck squamous cell carcinoma have been rapidly updated. Cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are gaining significant attention as potential chemopreventive agents. Both COX-2 and EGFR are involved in head and neck carcinogenesis. Targeting COX-2 and EGFR separately has shown promising antitumor activity. Recently, combinations of COX-2 and EGFR tyrosine kinase inhibitors have been reported to show synergistic/additive effects in preclinical studies. Because COX-2 and EGFR tyrosine kinase inhibitors are toxic as single agents in clinical trials, the combination of COX-2 and EGFR tyrosine kinase inhibitors used at lower doses seems more promising than monotherapy with either as a novel strategy in head and neck cancer chemoprevention.