The importance of medical research to the diagnosis and treatment of human diseases is well recognized. The use of human subjects, however, presents complex legal and ethical challenges for the scientific community and for society. The history of research performed on children reveals an especially vulnerable population needing special protection against violation of individual rights and exposure to undue risk. The development of guidelines and policies to protect children as research subjects is reviewed. Special focus is given to the present federal regulations that are intended to provide an ethical context for the performance of pediatric research, including the distinction between therapeutic and nontherapeutic studies. In part, these guidelines represent a return of the pendulum to a more moderate position, after an era of restrictive regulations in reaction to past abuses of children as research subjects. As a result, federal and professional initiatives are bringing renewed focus on the need for rigorous study of childhood development and disease within an appropriate ethical framework.