HRQOL assessment in patients with rare diseases can help to identify health needs, to evaluate the impact of disease and treatments, and to assess the evolution in health status through the natural history of disease. Several studies have shown that although some rare diseases do not necessarily affect life expectancy, the majority lead to physical, emotional and/or psychosocial limitations with a wide range of disabilities. Reliability as well as content, criterion, and construct validity, and also responsiveness should be taken into account in selecting the instrument to be used assessing individuals with rare diseases. The use of proxy-report may be essential in some cases where the patient is cognitively impaired or unable to communicate. Criteria for selecting a HRQOL instrument, as well as the more common strategies proposed help interpret scores on HRQOL instruments are addressed in the chapter. Given the impact of rare diseases on the quality of life of both patients and carers, it is likely that interest in its measurement will continue to increase among professionals, patients, and the general public. Improving the quality of life of people with rare diseases should be one of the most important goals of any health care intervention or multidisciplinary approach.