With its high rates of chronicity and concomitant economic costs to society, depression ranges among the most prevalent mental disorders. Several trials have succeeded in demonstrating the beneficial effects of early depression prevention programs for otherwise healthy children and adolescents. However, comparable programs for children and adolescents with a medical condition are still scarce. This paper discusses the situation of chronically ill children and adolescents who are at risk of developing comorbid depressive symptoms using the example of three conditions frequently encountered in pediatric psychosomatic medicine: diabetes, epilepsy and inflammatory bowel disease (IBD). Each patient group is introduced with regards to specific risk factors and correlates of depression. Also, existing customized depression prevention programs and according research trials are presented. Reviewing the body of literature, it becomes apparent that risk factor research and depression prevention are still in their infancy for these three patient groups. While new risk factor models and biomarker approaches emerge as a promising rationale for depression prevention, research is called upon to include randomized control trials as well as longitudinal designs in order to achieve more optimally tailored preventive interventions for children and adolescents with chronic medical conditions.