Abstract The concept of assessing health-related quality of life has a brief and vibrant history. In this monograph, theoretical issues related to the term and the reasons assessment of quality of life is important are discussed. There is a great deal of ambiguity surrounding definitions of the concept. This equivocation is caused in part by the fact that thinking on both the concept of health-related quality-of-life assessment and the way in which it should be measured are still evolving. Methodologic concerns regarding the assessment of health-related quality of life are discussed, including ways in which the validity and reliability of measurement approaches are established. These characteristics are important because they are necessary to ensure that accurate information is obtained with whatever instrument or procedure is used. Many significant issues relate to the use of quality-of-life assessment, and these are delineated. Consideration and resolution of these issues are prerequisites to the introduction of a given assessment instrument or procedure into a study. A large section of this article is devoted to a review of selected measures of health-related quality of life. Three types of measures are discussed. The first type is referred to as general. These measures are designed to be used across different diseases, different treatments or interventions, and different groups of patients. The reliability and validity of general instruments or procedures, plus their history of empirical use, make them invaluable methods of measurement. The second type of measure is referred to as disease specific. These measures are designed to assess specific diagnostic or patient populations with the goal of detecting responsiveness or clinically significant changes. The ability to assess such changes in a particular patient population has led to major growth in the development and introduction of these instruments in the past few years. The final type of measure consists of batteries of separate instruments that are scored independently. The advantage of using this approach is that the battery can be put together to assess whatever aspects of health-related quality of life need to be measured. Examples of quality-of-life assessment in medical research include a discussion of how various procedures are used to measure the construct with asthma, chronic respiratory disorders, and human immunodeficiency virus (HIV) disease. All three types of assessment—general, disease specific, and batteries of measures—have been used in this respect. Newer methods of assessment, particularly disease-specific instruments and procedures, are also described. General recommendations are offered to clinicians who may wish to include quality-of-life assessment in their research. This article concludes with a description of trends observed in quality-of-life assessment. We note that although no single gold-standard measure is apt to emerge for assessing quality of life, some general instruments are gaining wide acceptance. In addition, the proliferation of disease-specific instruments is noted. Finally, we discuss evidence that two trends—linking quality of life to economic indices and to the development of more complex models of assessment—will continue to expand both the arsenal and the application of health-related quality-of-life measures.