Oral submucous fibrosis (OSF) is a chronic disease of the oral mucosa characterized by inflammation and a progressive fibrosis of the lamina propria and deeper connective tissues. It is a condition predominantly seen among people of Indian origin, and an epidemiologic survey done a decade ago showed no less than 250,000 cases in India, a figure that must have increased sharply. OSF is a condition with a high risk of malignant transformation; to date, no conclusive etiologic agent has been identified, although plenty of data have been generated on various aspects of the disease. These include genetic, carcinogenic, immunologic, viral, nutritional, and autoimmune possibilities, all of which also have been implicated in the development of oral cancer. This article reviews existing evidence on the pathogenesis of OSF and its relation to oral cancer and suggests a possible multifactorial model to explain the disease process.