Oral potentially malignant disorders form a group of visible mucosal abnormalities with an increased risk for malignant transformation to oral cancer. In the last few years major steps have been made in the categorization and definitions of these lesions. In addition, important steps were made in predicting risk for malignant transformation, although multicenter validations are still required. A major problem at present is the lack of effective treatments. Despite surgical interventions, lesions recur and progress to cancer. This is further hampered by the fact that besides these visible lesions, mucosal changes may occur that are macroscopically not visible, but present only as microscopic morphological changes or can be identified by genetic aberrations usually in the resection margins of surgically treated oral cancers. Mucosal abnormalities, visible or not, cause primary tumors but also local relapses and second primary tumors in treated oral cancer patients. This indicates the need to focus on the development of novel and effective treatments.