Oral submucous fibrosis (OSF) is a chronic debilitating disease and a premalignant condition of the oral cavity. It is characterized by a generalized submucosal fibrosis. The pathogenesis of the disease is not well established. Epidemiological evidences strongly indicate the association of the betel quid (BQ) habit and OSF. Various findings indicate the disease to be a consequence of disturbances in the homeostatic equilibrium between synthesis and degradation of extracellular matrix (ECM), wherein collagen forms a major component, thus can be considered as a collagen-metabolic disorder. Transforming growth factor-beta (TGF-beta) is a potent stimulator of production and deposition of the ECM. The objectives of this review are to highlight the molecular events involved in the overproduction of insoluble collagen and decreased degradation of collagen occurring via exposure to BQ and stimulation of the TGF-beta pathway, and elucidate the cell signaling that is involved in the etiopathogenesis of the disease process.