Tobacco-related cancers exact an enormous toll in the United States and worldwide. The NCI's commitment to tobacco-related research should be commensurate with the health burden caused by tobacco use. There is now an unprecedented opportunity to accelerate groundbreaking research that can prevent cancer associated with tobacco use. This report reflects the consensus of leading scientists and experts regarding tobacco-related research priorities. It embodies a comprehensive set of research opportunities with nine overarching research priorities. These opportunities cover the range of tobacco control research from basic biological and basic biobehavioral research to clinical, policy, epidemiologic, and surveillance research, as well as support for research infrastructure. The research priorities presented in this report also emphasize the unique opportunities and challenges of tobacco initiation, use, addiction, and cessation among youth and populations at disproportionate risk. It was the unanimous and fundamental conclusion of the Tobacco Research Implementation Group that an unequivocal commitment of the NCI to a comprehensive, focused program of research on tobacco use can help to reverse the epidemic of tobacco-related cancers.