Health-related quality of life (HRQOL) is increasingly assessed to understand the effects of cancer and cancer-related interventions. At the macro level, monitoring HRQOL in the population and in cancer survivors may be important to track progress against cancer and evaluate the outcome of policies and programs. At the meso level, where most research, to date, has been focused, HRQOL data may be used in descriptive and analytic studies to understand the impact of cancer, patterns of care, and effects of interventions for cancer prevention, treatment, and continuing care. At the micro level, HRQOL data can inform individual patient and clinician decision making. Current data show that validated and commonly used HRQOL questionnaires are not interchangeable. Consequently, in determining which HRQOL measures are most appropriate for a given application, it is especially important to carefully consider both the study hypotheses and patient population. Future progress at all levels requires better understanding of the meaning and interpretation of HRQOL scores.