Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide. In the oral cavity, most cases of squamous cell carcinoma begin as a precursor lesion classified by the World Health Organization (WHO) as an “oral potentially malignant disorder (OPMD).” Oral leukoplakia is the most common OPMD, with a global prevalence of 4.1% and a malignant transformation rate between 0.1%-34.0%, and the malignant transformation rate increases to 40% in oral dysplasia. These wide ranges of malignant transformation rates suggest an unmet need to develop prognostic biomarkers that can better differentiate benign from premalignant lesions and predict the risk of transformation of premalignant lesions to invasive cancer. To address this major knowledge gap, the NIDCR partnered with the NCI Early Detection Research Network (EDRN) to bring together leading investigators to form a national network of Advancing Head and Neck Cancer Early Detection Research (AHEAD). In this session, we will highlight the efforts and advancements made in the field of early-stage detection and prevention of head and neck cancers. The learning objectives for the session are to: a) Review the current standard of care for patients diagnosed with OPMD; b) Identify the current challenges in diagnosing oral premalignant disease and; c) Explain three methodological and technological approaches being investigated for the early detection and prevention of HPV-positive and HPV-negative head and neck cancers.