Understanding the relationship of chemicals to carcinogenesis has progressed significantly since the initial observations of Hill and Pott in the 1700's. Distinguishing between DNA-reactive chemicals and those which increase cancer risk by increasing cell proliferation has been a major breakthrough in delineating overall mechanisms. Competing processes for activation versus inactivation of chemicals occur at many levels, including metabolism, DNA repair, and cellular repair processes. These processes can be affected by other agents to decrease carcinogenesis (chemoprevention). Increasing knowledge of the multiple steps of carcinogenesis is leading to improved methods for screening chemicals for carcinogenic activity and for regulatory decision making. Improvements in assessment of modes of action involved in animal and in vitro models have led to more rational approaches to assessing relevance to humans. The advent of genomics and high-throughput technologies have contributed to investigations of mechanisms and is beginning to impact development of better methods for screening chemicals. Based on developments in basic research, epidemiology, and astute clinical observations, the major risk factors and etiologic agents have been identified for a majority of cancers, which is beginning to lead to methods to decrease cancer incidence overall and identify targets for early detection and treatment.