Designing clinical trials to include patient populations most likely to demonstrate a response to the therapy being studied is not a new concept. The term “enrichment” refers to the prospective incorporation of clinical trial design elements intended to maximize the likelihood of observing a drug’s treatment effect (if, in fact, the drug is effective), and has been a focus area of the US Food and Drug Administration (FDA) since 1994. Enrichment strategies have been promulgated by the FDA over the ensuing decades, culminating in the 2012 FDA Guidance for Industry: Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products. A variety of enrichment strategies exist, including those intended to 1) reduce nondrug-related variability (practical enrichment); 2) increase the incidence of clinical events of interest (prognostic enrichment); or 3) select patients most likely to respond to treatment (predictive enrichment). All of these maneuvers are intended to increase study power to detect an investigational drug’s treatment effect. Enrichment may, therefore, be particularly valuable when there are a limited number of patients available for study, or when there have been difficulties in achieving successful clinical trials for a therapeutic indication. Both situations fit pediatric drug development today.