Health-related quality of life (HRQoL) is increasingly recognized as an important outcome in the treatment of advanced non-small-cell lung cancer (NSCLC). This article reviews HRQoL data from a literature search that identified 32 randomized trials of conventional chemotherapy in patients with advanced NSCLC. In common with much of the research in this area, interpretation of the data from some trials was limited by weaknesses in data collection and reporting of HRQoL results. Nevertheless, the trials comparing chemotherapy with best supportive care consistently identified that some components of HRQoL improved with chemotherapy, despite the associated toxicity of many of the regimens used. Novel targeted therapies promise efficacy without the toxicity typically observed with conventional chemotherapy, and this article also reviews HRQoL data from trials of gefitinib (IRESSA), the first epidermal growth factor receptor tyrosine kinase inhibitor to have demonstrated prospectively defined, clinically meaningful improvements in disease-related symptoms and HRQoL in patients with advanced NSCLC. In all trials reviewed, HRQoL findings to date support the incorporation of well-validated measures of HRQoL and symptom improvement in all future trials of drug therapy in advanced NSCLC patients. Ideally, the trials should have a prospectively defined HRQoL hypothesis, include measures to improve compliance with HRQoL assessments, and address the clinical meaning of the HRQoL findings.