Over recent decades, health-related quality of life (HRQOL) research has been increasingly integrated into cancer clinical trials. The purpose of this review is to examine the overall approach taken towards clinical trial-based HRQOL investigations within the European Organisation for Research and Treatment of Cancer (EORTC). This article reports a literature review of clinical trial-based HRQOL investigations and provides selective examples of HRQOL studies in phase III clinical trials in various disease sites. The findings of this review highlight that, historically, assessing HRQOL was a challenge. However, as EORTC has become more experienced in the assessment of HRQOL and has developed a portfolio of appropriate tools, HRQOL has become a more accepted end point in large-scale trials. The trials reviewed in this article show that, in general, HRQOL data do provide information that can both inform clinicians about the effectiveness of the treatments and also serve as an invaluable source of information for patients to make informed decisions regarding the treatment choice.