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The carcinogenicity hazard of chemicals in humans has been determined primarily on the basis of long-term animal testing. As progress has been made in determining the modes of action (MOAs) of chemicals that produce neoplasia in animal assays, it has become clear that there are qualitative and quantitative species differences between laboratory animals and humans, and it has become increasingly important to evaluate the relevance of these MOAs to humans. In this review, we discuss the usefulness of a framework for assessment of MOAs of nongenotoxic and genotoxic carcinogens and its human relevance, and remaining challenges to quantitative assessment of human risk.