Achieving proper balance between the social good that comes from performing research that involves children and offering the appropriate level of protection to children who participate in research is a significant challenge. As investigators design and implement research protocols, they should be aware of the ethical and legal requirements that govern research with human participants. This is especially true of research that involves children and other vulnerable groups. The welfare of children participating in research depends on knowledgeable, caring, and responsible investigators who place the well-being of the research participant above all other aspects of the research project. The purpose of this article is to provide a brief overview of the history of research involving children, to provide a basis for understanding the context within which the current federal regulations were written, and to provide an overview of the regulatory requirements that relate to research involving children. Good research is ethical research, and that requires investigators who take seriously the importance of participant welfare, meaningful informed consent, and respect for research participants.