Oral leukoplakia, a heterogeneous group of lesions, demonstrates a varying degree of risk for cancer progression. Histology (presence and degree of dysplasia), the current gold standard for assessing this risk, is reasonably effective in judging the malignant risk of high-grade pre-invasive lesions. It is, however, a poor predictor for lesions without dysplasia, or with minimal dysplasia, as only a few of these lesions will progress to cancer. This poses an enormous dilemma for clinicians as to whether these lesions should be aggressively treated or not. Recent studies show that loss of specific chromosomal regions (loss of heterozygosity, LOH) that contain known or presumptive tumor suppressor genes is an early predictor of subsequent progression of oral premalignant lesions. Incorporation of LOH findings into staging of oral premalignancy could improve our ability to identify and manage high-risk premalignant lesions, particularly those with relatively benign histology but high-risk genetic changes (high-risk LOH pattern).