Head-and-neck cancer is a disfiguring disease with increasing incidence rates even in young people, whose exposure to known risk factors is limited. This emphasizes the importance of early identification, on an individual basis, of precursor lesions that will develop into carcinomas. The clinical value of identifying individuals at high risk of oral cancer is emphasized by the fact that these patients are likely to benefit from available chemopreventive measures, largely without adverse effects. © 2002 Wiley-Liss, Inc. Key words : premalignant oral lesion; cancer risk; early diagnosis; prognosis; DNA ploidy; gross genomic aberration; chemoprevention; Oral squamous cell carcinomas have high mortality and morbidity and afflict an estimated 500,000 patients annually worldwide. [1][2][3][4] The incidence of oral carcinomas is especially high and increasing in developing countries. However, it is also increasing in Western countries, 5 substantially among younger people. 6 -8 Most cancers of the oral cavity are preceded by readily detectable white or red patches in the mucosal lining. The simple and straightforward detection of putative premalignant lesions gives a unique opportunity for identification of a malignant process and curative intervention at an early stage of oral carcinogenesis. Despite important advances in the field of head-and-neck oncology over the last decade, 9,10 identifying the subset of oral lesions that will progress to oral squamous cell carcinomas has remained a challenge. Reliable identification of lesions that are destined to become invasive cancers is possible. 11,12 Progress in determining the malignant potential of oral lesions allows more efficient chemopreventive treatment. 13 This review focuses on some diagnostic possibilities in premalignancies of the head and neck and on aspects of their molecular biology that may influence therapeutic approaches.PREMALIGNANT LESIONS OF THE ORAL MUCOSA Leukoplakias are frequently encountered lesions with a documented potential for transformation into oral squamous cell carcinomas. 14 -17 Erythroplakias, which are far rarer than leukoplakias, are considered to have a higher rate of malignant transformation (in some reports as high as 90%). 15 Detection of red or white patches does not require very sophisticated equipment or a particularly high degree of compliance from the patient. Since the days of Virchow, considerable knowledge of the morphologic manifestations of malignant genotypic changes has accumulated. In lesions of the oral cavity, the histologic finding of dysplasia has been considered to signal increased risk of malignant transformation. However, there is considerable uncertainty in the classification and grading of oral dysplasia, 18 -20 and several studies suggest that early and significant genetic changes do not necessarily correlate with observable morphologic changes within the mucosa. 11,12 Such changes have been detected and shown to signal subsequent transformation into manifest carcinoma, even in lesions classified as bei...