Recent epidemiologic data on the stabilization of adult and youth smoking rates underscore the need for vigorous research across the cancer control spectrum on tobacco use interventions. The steady decline in adult rates of smoking has stalled for the first time in 8 years, and certain race, ethnic, and population groups are disproportionately at risk to tobacco-related cancers because of disparities in tobacco use or access to effective interventions. Although substantial progress has been made across levels of basic through applied research, tobacco-control research across the discovery and delivery continuum must be accelerated to further reduce the cancer burden. Following a brief review of the prevalence and trends affecting tobacco use initiation and cessation, we identify and describe four domains of extraordinary research opportunities: genetics and gene-environment interactions, bioinformatics and health informatics, disparities and disproportionate risk, and prevention and treatment. Evolutionary scientific changes, like rapidly advancing technology and emphasis on the paradigm of team science research approaches, provide both a challenge as well as unparalleled opportunities for scientific advancement and public health progress.