Background Asthma is the most common chronic respiratory disease in children and adolescents. While most patients achieve good control with guideline-based treatment, a significant proportion experience persistent symptoms, frequent exacerbations, and impaired quality of life. Objectives This guideline aims to define severe and difficult-to-treat asthma in children and adolescents, support diagnostic precision, and provide practical, evidence-based recommendations for assessment and management, including biological therapies. Materials and methods The S1 guideline was developed under the coordination of the German Society for Pediatric Pulmonology following AWMF procedures. A structured consensus process involving experts from pediatric pulmonology, allergology, and general pediatrics was conducted. Existing national and international guidelines and new evidence were systematically reviewed and adapted. Results Key elements include a stepwise diagnostic algorithm to distinguish difficult-to-treat from truly severe asthma, guidance on assessing adherence, comorbidities, and inflammation biomarkers, and recommendations for targeted biological treatment. This guideline addresses monitoring tools, transition to adult care, and the role of rehabilitation. Conclusions Children and adolescents with severe asthma require early referral to specialized centers and a structured, interdisciplinary approach. Personalized treatment strategies—including biologics—should be guided by phenotyping and biomarkers. Registry data are essential to improve care quality and generate real-world evidence.