Quality of life (QOL) is an often-used but it remains an ill-understood concept in medicine. Literature suggests 3 important approaches to operationalize and measure QOL: Health-related quality of life (HRQOL), well-being, and QOL as a superordinate construct. To measure the various instruments of HRQOL (SF-36 and Sickness Impact Profile) and well-being (Satisfaction With Life Scale and Life Satisfaction Questionnaire LiSat) are used. Domains on which QOL of persons with SCI lag behind QOL of the general population are identified. Overall, this paper suggests: (1) that inspection of the QOL measure used in a particular study is necessary to identify the domains of QOL that are measured, (2) that most measures lack sufficient evidence of reliability and validity, and (3) that longitudinal studies starting in the early phase of rehabilitation are necessary to reveal the course and predictors of QOL of persons with SCI.