Head and neck squamous-cell carcinoma (HNSCC) is the sixth most common cancer worldwide and, disappointingly, survival rates are not improving. Moreover, HNSCC has a severe impact on the quality of life of patients and survivors, and the significant morbidity subsequent to treatment often mandates long-term multidisciplinary care, which places significant financial pressures on the treating institution. Therefore, prevention and early diagnosis of high-risk pre-malignant lesions are high priorities for reducing deaths due to head and neck cancer. Recent advances have begun to elucidate the different aetiologies of HNSCCs in relation to previous pre-malignancies and to identify which pre-malignant lesions are likely to progress to malignancy.