Purpose: United States (US) Pediatric Legislation (PL) was introduced in 1997 to improve children's health. The European Union PL (EUPL) has been in force since 2007. Both PLs facilitate additional pediatric research on primarily adult drugs. The EUPL declares that the forces of the market are not sufficient for children. Without a pediatric investigation plan, new drugs can no longer be registered with the European Union. New ways on how to facilitate drug development for rare pediatric diseases are being proposed. Methods: US PL, EUPL, and implications of modern labels for medical decision making are discussed. Findings: Modern drug labels constituted a step from eminence-based towards data-based medical decision making. However, approval by regulatory authorities did not replace knowledge transfer in medicine, which continued in university education, through conferences, consensus papers, and so on. Children were successfully treated with off-label drugs in pediatric oncology and in many other diseases. Describing children as "therapeutic orphans" reflected an overestimation of drug labels and an underestimation of nonregulatory systematic clinical testing. Therapeutic breakthroughs have occurred, for example, in acute myelogenous leukemia and cystic fibrosis. Rare diseases need new innovative drugs and therapeutic concepts for further breakthroughs. (C) 2017 Elsevier HS Journals, Inc. All rights reserved.