Tobacco is a leading contributor to morbidity and mortality and a primary reason for health disparities among African Americans. In this study we explore the role of stress in smoking and cultural factors that protect against stress among African-American adolescents. Our sample consisted of 239 youth who were recruited into the study while enrolled in 8th and 12th grade. Measures of risk factors (stress, school transition stress, and community disorganization), moderator or protective factors (religious support and intergenerational connections), and 30-day tobacco use were collected. Hierarchical multiple regression analyses were conducted. Intergenerational connections moderated the effect of stress on past 30-day tobacco use. Religious support moderated the effect of neighborhood disorganization on past 30-day tobacco use. Religious support also moderated the effect of stress on past 30-day tobacco use. The findings have implications for prevention efforts to consider religious beliefs and practices and also to link youth with supportive adults in their community. (Contains 2 tables.)