Oral cancer is one of the 6th most common cancer in the world. It causes considerable morbidity with a 5 year survival rate of 40-60%. The development of an effective chemoprevention agent for head and neck squamous cell carcinoma (HNSCC) has made limited progress over the past three decades. Many micronutrients have been tried as a chemopreventive agents like vitamin A, E, curcumin and dietary agents. Due to the disappointing outcomes of those agents the molecular agents have come into play. Hence, in this review, we summarize the biological basis of HNSCC chemoprevention i.e., molecular target interventions by COX-2 and EGFR inhibition. Finally we introduce the concept of green chemoprevention, interventions based upon whole plant foods or simple extracts that may become cost effective option for the next generation of studies.