The health-related quality of life (HR-QOL) of children and adolescents is increasingly considered a relevant topic for research. Instruments to assess quality of life in children and adolescents of a generic as well as disease- or condition-specific nature are being developed and applied in epidemiological surveys, clinical studies, quality assurance and health economics. This paper attempts to give an overview on the state of the art of HR-QOL assessment in children as it relates to methodological and conceptual challenges. Instruments available in international or cross-cultural research to assess HR-QOL in generic terms were identified and described according to psychometric data provided and the width of application. In an initial literature search, several challenges in the assessment of child and adolescent HR-QOL were identified, ranging from conceptual and methodological to practical aspects. Seven specific major issues were considered: (i) What are the dimensions of HR-QOL relevant for children and adolescents, and do suitable instruments for their measurement exist? (ii) Can these dimensions be collected in a cross-culturally comparable way? (iii) What advantages and disadvantages do self-rated versus externally evaluated HR-QOL measurements of children and adolescents have? (iv) How can HR-QOL be assessed in an age-appropriate way? (v) What are the advantages and disadvantages of disease-specific and generic data collection? (vi) What advantages and disadvantages do profile and index instruments have? (vii) How can HR-QOL be connected with utility- preference values? In a second literature search we identified nine generic HR-QOL instruments and four utility health state classification systems that complied with the prespecified inclusion criteria. It was concluded that (i) HR-QOL instruments are available to assess the dimensions of the construct relevant to children and adolescents; (ii) provided that an instrument was constructed in an appropriate way, the dimensions of HR-QOL can be measured in an interculturally comparable manner; (iii) the HR-QOL of children and adolescents can and should be ascertained by self-rating; (iv) the measurement instruments used have to consider maturity and cognitive development; (v) only generic quality-of-life instruments allow for an assessment of HR-QOL in both healthy and chronically ill children and adolescents; (vi) the representation of HR-QOL achieved through a singular index value is connected to strict psychometric conditions: the index instrument has to be tailored to these psychometric conditions; (vii) how far utility measures are employable with children and adolescents has to be investigated in further studies. The problem aspects identified indicate the necessity for further research. Nevertheless, instruments for assessing the HR-QOL of children and adolescents can be identified that meet the requirements mentioned above.