Health-related quality of life (HRQOL) and other types of patient-reported outcomes (PROs) are now important outcome measures in cancer clinical trials. A number of potentially less toxic drugs are available, and newer treatments can potentially offer cancer patients the possibility to be treated with less aggressive approaches, making PROs more critical in evaluating treatment effectiveness. However, assessing PROs in clinical trials requires careful consideration of a number of methodological issues. Robust methodology and accurate reporting of results are crucial to provide the scientific community and health care providers with a transparent message about the impact of a given drug or a new medical approach on patients' health status. This paper provides basic guidance on methodological issues to be addressed when designing and reporting HRQOL in clinical trials and presents examples of relevant brain cancer studies.