In addition to mortality, morbidity, and patient satisfaction, health-related quality of life (HRQOL) is an outcome of health care as well as a consequence of illness or injury. Consequently, instruments to assess HRQOL have become important outcome measures for the evaluation of health care. The last 2 decades have seen the development of hundreds of HRQOL instruments, which are increasingly being incorporated in clinical trials. However, for HRQOL instruments to be valid outcome measures, a variety of factors must be addressed, including conceptual and methodological issues. In addition, there must be careful selection and thoughtful administration. The present report discusses these issues in addition to the scoring and interpretation considerations for the valid assessment of HRQOL. We provide an overview of generic, disease-specific, and utility measures. Using disease-specific instruments pertinent to respiratory care, we discuss their validity, reliability, responsiveness, and minimum clinically important difference. We conclude with recommendations regarding which HRQOL tools have documented evidence that they are psychometrically sound for application to research and clinical practice in respiratory care.