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This review summarizes recent studies on the feasibility, reliability and validity of pediatric health-related quality of life questionnaires and gives an overview of recent applications of these measures in pediatrics.The often-applied short form of the Child Health Questionnaire (CHQ-PF28) provides reliable physical and psychosocial summary measures, but reliable estimates for each scale require the longer version (CHQ-PF50). In addition to this questionnaire, the Pediatric Quality of Life Inventory is another reliable and valid measure. The TNO-AZL Preschool Children Quality of Life questionnaire is a feasible and reliable measure for preschool children. Generally, generic questionnaires are less sensitive to the impact of specific diseases than are disease-specific questionnaires. Parent and self-reports provide different outlooks on quality of life, which complement each other.There are several feasible, reliable and validated pediatric quality of life questionnaires that can be used in clinical trials. These include generic and disease-specific questionnaires and health profile measures, as well as preference-based measures in pediatric settings. Generally, a combination of these types of questionnaires would be the most appropriate approach. Moreover, a combination of parent and self-reports should be applied. Appropriate selection of outcome measures will enhance the quality of pediatric studies and the ability to assess treatment effects in clinical trials.