Measuring the quality use of medicines can be conceptualized as a mechanism for understanding appropriate use, underuse, overuse, or misuse. For pediatric pharmacotherapy, measuring the quality use of medicines requires awareness of the differences in health care between children and adults and the differences in the quality and quantity of science that supports evidence-based practice in pediatric health care compared with adult health care. Here we use the Pediatric Quality Measures Program that arose from the Children's Health Insurance Program Reauthorization Act in the United States to illustrate the challenges in developing quality measures of pediatric pharmacotherapy. The challenges are primarily twofold: (i) weak evidence base for the specific pharmacotherapy in children and (ii) limited data to calculate the measure. A weak evidence base must often be weighed against the importance of the topic if the quality measure is intended to address a known quality of care or public health problem. Limited data because of insufficient amount or inappropriate type will affect implementation of the measure and its eventual usefulness. Methods to meet these challenges often depend on the priorities of and the tools available to end users. Health information technology is emerging as a tool to improve quality measurement but presents additional challenges.