OBJECTIVE: Cigarette smoking and other forms of tobacco use are addictive and harmful. Though no level of smoking is safe, children and adolescents who are medically at-risk due to the presence of a chronic or life-threatening disease may be especially vulnerable to these dangers. This article provides an overview of considerations in the prevention of tobacco use in this special population. METHODS: This article summarizes medical aspects of childhood chronic disease and the impact of cigarette smoking, the prevalence of tobacco screening in pediatric healthcare, and levels of prevention for individuals, families, schools, and healthcare. Recommendations for clinical services and research are also included. RESULTS: There are a number of reasons to prevent and interrupt the onset of smoking in medically at-risk youth. Subspecialty clinics appear to be the most likely point of entry for prevention-based work in this area. However, no one single setting will be effective in preventing and deterring use without due consideration of other settings, perspectives, and influences on smoking uptake. CONCLUSIONS: The promise of smoking prevention to improve the health and outlook of children and adolescents with chronic or life-threatening disease is high, and additional efforts are needed for this population.