Editors' Summary: This Dialogue addresses whether a single exposure to a carcinogenic agent can cause cancer. Using a database that contains nearly 5,000 studies that have assessed the ability of a single dose of a chemical to cause cancer, the authors discover that approximately 400 chemicals representing more than 30 chemical classes have been found to cause tumor development. These chemicals have been shown to induce tumors in numerous animal models, including more than 400 mouse and 100 rat strains, as well as in less frequently used models such as hamsters, guinea pigs, gerbils, rabbits, primates, and several fish species. Similarly, this phenomenon has been found in numerous tumor types, through multiple routes of exposure, in both genders, and during various stages of development and maturation. The authors argue that a single dose need not be exceedingly high nor approach acute toxicity in order to cause cancer. The implications of these findings for carcinogen testing and risk assessment procedures, particularly those concerning less than lifetime exposures, are also addressed in light of potential mechanistic interpretations by which single dose carcinogens can act. The authors conclude that episodic exposures to short-term high exposures may be an important yet generally overlooked area of concern.