Tumors arise from single cells that acquire the ability to proliferate when their neighbors cannot. A series of evolutionary steps then follows by which cancer cells gain the means to escape the confines of the tissue they originate in, to survive in the circulatory systems of the body, and finally, to colonize distant sites. In this section, we examine the process of tumorigenesis. We first ask how carcinogens can induce tumorigenesis. We then introduce a hypothesis, known as the multi-hit model of cancer, that explains not only the multistep path of the disease, but also the fact that cancer is largely a disease of old age. We conclude this section by discussing cell-based and mouse models that have been instrumental in elucidating the molecular basis of tumorigenesis.