The PedsQL 4.0 (Pediatric Quality of Life Inventory) Generic Core Scales are child self-report and parent proxy-report scales developed to measure health-related quality of life (HRQOL) in children and adolescents ages 2-18. The PedsQL 4.0 Generic Core Scales consist of 23 items applicable for healthy school and community populations and pediatric populations with acute and chronic health conditions. The 4 PedsQL 4.0 Generic Core Scales (Physical, Emotional, Social, School) were administered to 209 children and 269 parents (289 subjects accrued overall) recruited from pediatric cardiology, orthopedics, and rheumatology clinics. Sensitivity, responsiveness, and the impact on clinical decision-making were determined. The PedsQL was differentially sensitive to increasing degrees of cardiac disease severity in the cardiology clinic setting and responsive to clinical change over time in the pediatric orthopedics clinic setting. In the pediatric rheumatology clinic setting, the PedsQL demonstrated an impact on clinical decision-making, resulting in subsequent increases in HRQOL.