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Engaging in smoking is particularly risky for children and adolescents with chronic illness whose health status is already compromised because of disease- and treatment-related complications. Yet, some of these youngsters smoke at rates at least comparable to those of their healthy peers. To date, few randomized smoking-prevention and cessation trials have been conducted in children with chronic medical problems. In this review we report on the smoking rates among youngsters with chronic illness, identify specific disease- and treatment-related complications that can be exacerbated by smoking, examine risk factors associated with tobacco use among medically compromised youngsters, and review smoking interventions that have been conducted to date with pediatric populations in the health care setting. The following chronic illnesses are included in this review: asthma, cystic fibrosis, cancer, sickle cell disease, juvenile-onset diabetes, and juvenile rheumatoid arthritis. Objectives for a tobacco-control agenda and recommendations for future tobacco studies in chronically ill pediatric populations are provided. Finally, tobacco counseling strategies are suggested for clinicians who treat these youngsters in their practices.