Simple SummaryOral cavity is the most common site of head and neck cancer which is ranked as the eighth most common cancer worldwide. Oral cancer treatment is often associated with significant morbidity and is sometimes ineffective. These cancers, mainly due to tobacco and alcohol consumption, can develop from oral potentially malignant disorders, the most common of which is oral leukoplakia. Some of these oral potentially malignant disorders disappear, while others will transform to oral cancer. Patients may also develop cancer in the field of cancerization. Unfortunately, except for the surgical excision of lesions with dysplasia, there is no effective intervention to effectively prevent transformation or cancer development in the field of cancerization. Moreover, no standardized biomarker has been clearly identified as sufficient to predict malignant transformation. In this article, several experts discuss the main challenges in oral cancer prevention, in particular the need (i) to define new a new classification system integrating cellular and molecular features aiming (ii) at better identifying patients at high risk of malignant transformation, and (iii) at developing treatment strategies to prevent their malignant transformation of oral potentially malignant disorders.Oral potentially malignant disorders (OPMD) may precede oral squamous cell carcinoma (OSCC). Reported rates of malignant transformation of OPMD range from 3 to 50%. While some clinical, histological, and molecular factors have been associated with a high-risk OPMD, they are, to date, insufficiently accurate for treatment decision-making. Moreover, this range highlights differences in the clinical definition of OPMD, variation in follow-up periods, and molecular and biological heterogeneity of OPMD. Finally, while treatment of OPMD may improve outcome, standard therapy has been shown to be ineffective to prevent OSCC development in patients with OPMD. In this perspective paper, several experts discuss the main challenges in oral cancer prevention, in particular the need to (i) to define an OPMD classification system by integrating new pathological and molecular characteristics, aiming (ii) to better identify OPMD at high risk of malignant transformation, and (iii) to develop treatment strategies to eradicate OPMD or prevent malignant transformation.