Health-related quality of life (HRQOL) is increasingly seen as important to reflect the impact of an illness and its treatment on a patient from the patient's perspective. However, there may be times when it is difficult to obtain this information directly from pediatric patients, and parents are therefore used as substitutes. Nevertheless, an informant discrepancy between children and their parents increase the need to identify variables which contribute to the observed differences between children's self-reports and parents' proxy-reports. Discrepancies between child and parent reports have often been regarded as "methodological error" and have led to misconceived arguments about who is "right." The aims of this review are to provide an overview and update to help understand the relation between children's self-report of their symptoms and HRQOL and parents' proxy-reports, the circumstances in which informant discrepancies might be expected, and potential reasons for these discrepancies. Discrepancies can be summarized in relation to characteristics of the child, the adult and the HRQOL domain being measured. We conclude that informant discrepancy is not simply an irritating measurement error, but also has its clinical implications. We argue that parents and children base their judgments of pediatric HRQOL on different information and as such, comprehensive evaluation needs to take account of both perspectives. This perspective has implications for the design of clinical trials and necessitates routine collection of data from both sources in clinical research and practice.