The United States is undertaking a major expansion of comparative effectiveness research, with the potential to achieve systemwide improvements in health care quality, outcomes, and resource allocation. However, to achieve these improvements in children's health and health care, comparative effectiveness research needs to be targeted, designed, conducted, and reported in ways that are responsive to the unique circumstances of children and adolescents. These include clinically important differences in the type and course of disease in children; demographic differences between the overall child and adult population in the United States, such as racial and ethnic makeup; and methodological issues involving study design. Our overarching point is that the base of evidence in pediatrics must not fall even further behind that for the adult population in an era of rapid advancement and funding of comparative effectiveness research.