Context: Appalachia has high rates of tobacco use and related health problems, and despite significant impediments to alcohol use, alcohol abuse is common. Adolescents are exposed to sophisticated tobacco and alcohol advertising. Prevention messages, therefore, should reflect research concerning culturally influenced attitudes toward tobacco and alcohol use. Methods: With 4 grants from the National Institutes of Health, 34 focus groups occurred between 1999 and 2003 in 17 rural Appalachian jurisdictions in 7 states. These jurisdictions ranged between 4 and 8 on the Rural-Urban Continuum Codes of the Economic Research Service of the US Department of Agriculture. Of the focus groups, 25 sought the perspectives of women in Appalachia, and 9, opinions of adolescents. Findings: The family represented the key context where residents of Appalachia learn about tobacco and alcohol use. Experimentation with tobacco and alcohol frequently commenced by early adolescence and initially occurred in the context of the family home. Reasons to abstain from tobacco and alcohol included a variety of reasons related to family circumstances. Adults generally displayed a greater degree of tolerance for adolescent alcohol use than tobacco use. Tobacco growing represents an economic mainstay in many communities, a fact that contributes to the acceptance of its use, and many coal miners use smokeless tobacco since they cannot light up in the mines. The production and distribution of homemade alcohol was not a significant issue in alcohol use in the mountains even though it appeared not to have entirely disappeared. Conclusions: Though cultural factors support tobacco and alcohol use in Appalachia, risk awareness is common. Messages tailored to cultural themes may decrease prevalence.