Health-related quality of life (HRQOL) is an important measure of a patient's perception of his/her illness. Over the past 3 decades, numerous instruments have been developed to measure HRQOL in various patient populations, with 2 basic approaches: generic and disease-specific. While generic measures have broad application across different types and severity of diseases, disease-specific measures are designed to assess particular diseases or patient populations. All HRQOL instruments, however, must be valid and have high reliability and responsiveness. Validity ensures that the instrument measures what it is supposed to measure. Reliable instruments are able to reproducibly differentiate between subjects. Responsive evaluative measures are able to detect important changes in HRQOL during a period of time, even if those changes are small. HRQOL measures should also be interpretable, meaning that the differences in scores that correspond to small, moderate, and large HRQOL changes are easily identifiable. This article describes the steps in the development of HRQOL instruments from the conceptual framework to creation and testing. Several examples of generic and disease-specific instruments commonly used to evaluate HRQOL in patients with immune-mediated inflammatory diseases (IMID) are provided.