Health-related quality of life (HRQOL) is a multidimensional concept used to measure patients' functioning and well-being. In recent decades, HRQOL has become an important (secondary) outcome measure in clinical trials for brain tumor patients. It could be questioned, however, whether HRQOL is the only useful outcome measure for assessing the level of functioning and well-being of these patients. As described in this review, several general methodological issues can hamper the interpretation of HRQOL data collected in the oncology setting. Additionally, because brain tumor patients have a progressive brain disease resulting in cognitive impairments, patient-reported outcomes may not always be the most informative and accurate measures of HRQOL in brain tumor patients. Supplementary or alternative measures, such as proxy-rated HRQOL measures and measures of instrumental activities of daily living, may provide a more complete picture of brain tumor patients' functioning in daily life.