The National Cancer Institute's efforts to prevent tobacco-related cancers have resulted in numerous activities to reduce smoking prevalence throughout the United States. Two decades of research activity has provided much of the information needed for interventions through channels such as mass media, physician/dentist training, self-help strategies, and school-based prevention programs. However, in the area of adolescent tobacco-use reduction, it has been consistently observed that youth who have the highest tobacco-use rates are among those least likely to be reached through school-based or other programs. Thus, these youth, often labeled "high-risk," are seen as a cornerstone for tobacco use prevention efforts. Although they pose a particularly difficult access problem, many valuable recommendations for strategies to identify and reach this group were made by a recent NCI-convened Expert Advisory Panel on the Prevention and Cessation of Tobacco Use by High-Risk Youth. The Panel considered this issue from three perspectives--methods of identifying these youth, strategies for reaching them with appropriate tobacco-use prevention/cessation programs, and identification of research needs. Their recommendations and conclusions are summarized in this article. Support for research addressing the prevention and cessation of tobacco use among high-risk youth is currently being considered by the NCI.