Head and neck cancers, including varieties of oral cancers, can adversely impact the patients’ quality of life. Oral cancers could be preceded by visible intermediate clinical changes in the oral mucosa. With a progressive understanding of the premalignancy process, a terminology is specified and updated by WHO (2005) as to “Oral Potentially Malignant Disorders (OPMDs).” This includes varieties of precancerous lesions (i.e., oral leukoplakia and oral erythroplakia) and conditions (i.e., oral submucous fibrosis and lichen planus). Successful screening of OPMDs is very critical in the early detection, management, and prevention of malignant transformation. Conventional clinical examination has been supported with different vital staining, light-based detection systems, optical diagnostic technologies, and more recently potential molecular biomarkers. Future studies should focus on predicting the malignant potential of OPMDs with improved specificity and sensitivity. This would minimize the associated morbidities and mortalities of late detection of malignant changes that may progress to involve the head and neck region with metastasis.