Oral submucous fibrosis (OSF) is prevalent mostly in Southeast Asia, particularly in the Indian subcontinent. Chewing betel nuts and betel leaves, with or without tobacco, has been associated with OSF. Betel quid contents including guvacine, arecoline, guvacoline, arecaidine, and chavibetol are considered to play an important part in the occurrence of OSF. Transformation of OSF to squamous cell carcinoma (SCC) is variable, but up to 13% conversion of OSF to SCC has been reported. Various genetic and molecular mechanisms impact the malignant transformation of OSF, causing changes in the cell cycle, DNA, keratinocytes, and keratin; tumor-cell proliferation and survival; angiogenesis; fibrosis through epithelial-mesenchymal transitions (EMTs), and tissue hypoxia. All are reviewed here, including potential biomarkers for malignant transformation of OSF. These interactions are not fully understood, but a critical mass of knowledge is building up to ultimately allow the understanding of all mechanisms involved.