In the previous chapters, zero was often defined as the inability to experimentally detect a chemical or observe an adverse biological effect. When the chemical or effect was not detected, one could reasonably conclude nothing would happen. This approach worked for most drugs, consumer products as well as agricultural, and industrial chemicals. Carcinogens and mutagens that interact directly with DNA, represent a potentially different scenario because any available data connecting a chemical exposure to an induction of cancer, is usually at exposure levels far greater than that encountered in foods or the environment. Cancer often occurs much later than the original initiating chemical exposure, as promotion by a second compound may be required. Twentieth century toxicology has been criticized for conducting high dose studies using very few doses to predict very low dose rare effects. This chapter reviews the approaches to estimate a zero dose for exposure to carcinogens in both experimental animal and human epidemiological trials. It represents various regulatory endpoints created to define when a chemical is a carcinogen and how to extrapolate to essentially no risk; the primary issue in cancer risk assessment being how to extrapolate from available high dose data to the elusive zero dose.