Abstract: The National Toxicology Program rodent cancer bioassay program design evolved from that of the National Cancer Institute in the 1970s. Groups of 50 or more mice are assigned to control or treatment groups. Test substances are given at three dose levels by intubation, dietary or drinking water consumption, or dermal or inhalation exposure. Dosing starts at age 5–6 weeks and lasts for 2 years, when surviving animals receive a complete histopathologic examination. Statistical approaches accommodate survival differences and no longer require differentiation between fatal and incidental tumors. Photocarcinogenicity studies, employing SKH-1 hairless mice, evaluate onset of skin papillomas and incidences at 1 year. Top doses are chosen to expose animals to a minimally toxic challenge and lower doses to operate within the linear range of kinetics. This dosing allows comparison of results across studies. Bioassay and ancillary studies successfully identify tumor-causing agents in rodents, provide information on dose-response, and characterize other chemical-related toxicities. NTP and Ramazzini Foundation bioassay designs differ in several aspects, but bioassays at both institutions provide chemical-specific information for predicting human carcinogens, thus providing for protection of public health. Bioassays constitute an essential information reference set for new assay development and further investigations into mechanisms of action. The scientific community and the public owe a huge debt of gratitude to Dr. Cesare Maltoni of the European Foundation of Oncology and Environmental Sciences and to Dr. David P. Rall of the National Institute of Environmental Health Sciences for their foresight and wisdom in creating and nurturing these bioassay programs.