Health-related quality of life (HRQoL) denotes the patients' perception of well-being and function in physical, emotional, mental, social and everyday life areas. In adult medicine, HRQoL has been established as an outcome criterion to evaluate the quality and effect of different therapies. During the past 20 years, a multitude of instruments to assess HRQoL has been developed, mostly for adults, complying with psychometric standards concerning the reliability, validity and sensitivity of the scales. HRQoL research in children, however, is still in a developmental stage. The present paper describes challenges to the assessment of quality of life in children and adolescents: approaches to assess quality of life include patients' self-report versus report by other persons. Interviews, questionnaires and computer-assisted methods have been used. Generic and disease-specific (targeted) instruments can be applied. Frequently used generic measures are described and an international project to develop a set of quality of life instruments for children with chronic conditions is reported. The application of these measures in the research context using examples from a German prospective study in pediatric rehabilitation is exemplarily described and highlights the potential benefit of implementing these methods in epidemiologic and clinical studies.