It is necessary to determine whether chemicals or drugs have the potential to pose a threat to human health. Chemicals that can damage DNA are detected in short-term assays, but the detection of nongenotoxic carcinogens relies upon bioassays in laboratory animals. However, there are marked differences between rodents and humans in response to nongenotoxic carcinogens, which makes the relevance of rodent data to human risk assessment questionable. Here, we address the background issues concerning rodent nongenotoxic carcinogenesis and then focus upon peroxisome proliferators, chloroform, and dioxins as examples of toxicants that cause rodent-specific oxidative stress, cell proliferation, and the suppression of apoptosis. In the case of peroxisome proliferators and dioxins, this response is receptor-mediated. The evidence presented suggests that, at least for some toxicants, the molecular mechanisms of the rodent carcinogenic responses do not operate in humans; this is discussed in the context of human risk assessment. Finally, consideration is given to incorporating mechanism-based information into risk assessment for regulatory purposes.