Betel nut is a widely masticated natural product, which is consumed by over 600 million people across the globe. The ancient habit of betel nut chewing, either as dry or raw/wet nut, in association with betel leaf and a host of region specific additives, including chewing tobacco, is believed to be an important etiological factor for human cancer. Alkaloids and their betel nut specific nitrosamine derivatives produced upon metabolic activation interact with DNA and other cellular targets to produce highly variable mutagenic, genotoxic, cytostatic, immunostatic and teratogenic effects. At molecular level the betel nut or its constituents strongly influence gene expression patterns, especially that of tumor suppressor genes. Structural damage to nucleus and mitochondria, etc. are also induced. The review dwells upon these aspects of betel nut induced carcinogenesis to show that genetic susceptibility to cancer through generations progressively increased due to exposure to betel nut.