Evaluating health-related quality of life (HRQL) for children who have benign hematologic disorders can: (1) aid in the evaluation of different therapies and emerging new technologies; (2) serve as an invaluable source of anticipatory guidance, for current and future patients; and (3) serve an important evaluative function of clinical services or programs to identify potential areas in which additional services, supports, or interventions are needed. The past 20 years have been marked by the dramatic growth in the field of HRQL research, although much of the progress in conceptualization, instrument development, and refinement has occurred in adults. Pediatric health services researchers and their clinical colleagues have had to grapple with the methodologic challenges in evaluating HRQL in children. This article includes a discussion of instrumentation, respondent selection, and study design consideration in the evaluation of HRQL in children who have benign hematologic disorders.