Malignancies of the upper aero-digestive tract are a major public health problem, especially in South Asia. The major risk factors in South Asia remain smoked/smokeless tobacco, areca nut, alcohol abuse and poor diet, with limited evidence for human papillomavirus (HPV). Although HPV-associated head and neck squamous cell carcinoma (HNSCC) is well documented in the western world, studies on South Asian populations are few and inconsistent. However, the incidence of HPV-associated head and neck cancer (HNC) has increased in recent years. Certain high-risk types of HPV infection are regarded as well-established risk factors for cervical cancer and a subset of HNSCC; however, their true role and importance in the progression of HNSCC remain unclear. Although HPV-associated HNC patients generally have a better prognosis than those with HPV-negative disease, current chemo- and radio-therapies are largely non-specific and have considerable toxicities. RNA interference (RNAi), which has shown great promise as a highly specific therapy for other diseases, has potential for treating HPV-associated HNC, especially if disease progression is dependent on the continual expression of HPV oncogenes.