AbstractGlobally, oral cancer is one of the ten common cancers. In some parts of the world, including the Indian subcontinent, oral cancer is a major cancer problem. Tobacco use is the most important risk factor for oral cancer. The most common form of tobacco use, cigarette smoking, demonstrates a very high relative risk—in a recent cohort study (CPS II), even higher than lung cancer. In areas where tobacco is used in a smokeless form, oral cancer incidence is generally high. In the West, especially in the U.S. and Scandinavia, smokeless tobacco use consists of oral use of snuff. In Central, South, and Southeast Asia smokeless tobacco use encompassesnass, naswar, khaini, mawa, mishri, gudakhu, and betel quid. In India tobacco is smoked in many ways; the most common isbidi, others beingchutta, including reverse smoking,hooka, and clay pipe. A voluminous body of research data implicating most of these forms of tobacco use emanates from the Indian subcontinent. These studies encompass case and case-series reports, and case-control, cohort, and intervention studies. Collectively, the evidence fulfills the epidemiological criteria of causality: strength, consistency, temporality, and coherence. The biological plausibility is provided by the identification of several carcinogens in tobacco, the most abundant and strongest being tobacco-specificN-nitrosamines such asN-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). These are formed byN-nitrosation of nicotine, the major alkaloid responsible for addiction to tobacco. The etiological relationship between tobacco use and oral cancer has provided us with a comprehensive model for understanding carcinogenesis.