The incidence of SCCHN is expected to be approximately 42,800 new cases in the United States with more than 12,000 deaths from this disease for the year 2006. The five-year survival rate for patients with SCCHN in the United States and other developed countries is still poor, approximately 40%, and even those patients who do not experience recurrence of the original cancer, have a high risk of developing a second primary malignancy. Thus, a preventative approach before the development of invasive cancer is highly desirable and novel strategies to reduce cancer incidence in SCCHN and other tobacco-carcinogen related malignancies are being pursued. Ever since the last two decades have seen the rise and fall of the results of clinical trials using carotinoids and retinoids as chemopreventive agents, new treatment strategies are needed. Selective and nonselective COX-1/2 inhibitors and EGFR tyrosine kinase inhibitors have shown promising results in cancer therapy and are currently evaluated in chemoprevention trials. However, associated high costs and side effects make these less attractive to patients with premalignant lesions. Phytochemical containing foods like green tea, pomegranate juice and other natural compounds are attractive since they are less costly, nontoxic and widely available. While small trials have shown promising results using these agents, larger trials have yet to be conducted to establish chemopreventive effects. Since premalignant lesions of the oral cavity are easily accessible for topical treatments, it remains to be seen if there is a role for topical treatments. Current clinical trials using these novel agents for prevention of second primary tumors or treatment of premalignant lesions will further elucidate which agents should be used but also will help to establish the role of chemoprevention in head and neck cancer.