Background: Institutional review boards (IRBs), duly constituted under the Office of Human Research Protection, have the federally mandated responsibility of reviewing research involving human subjects to ensure that a proposed protocol meets the appropriate ethical guidelines before subjects may be enrolled in any study. The road leading to the current regulations and ethical considerations has been long and checkered. Methods: This paper reviews the history of human subjects participating in research, including examples of egregious events, and the ethical analyses that precipitated the evolution of the mandated protections afforded participants in research under current federal regulations. Results: Key documents-from the Nuremberg Code in 1947 to the Belmont Report in 1978 to Moral Science: Protecting Participants in Human Subjects Research in 2011-that have informed the ethics debate regarding human subjects protection in research activities are presented in light of their historic significance, highlighting the complexity of the issues surrounding protection of human subjects in research. Conclusion: The examples from history and the scarcity of contemporary examples demonstrate that the regulations for the protection of humans participating in research have evolved in a way that minimizes the probability that subjects will be harmed when they choose to participate in research. The examples also reinforce the importance of individual responsibility. Failure of IRBs to provide appropriate review and oversight can lead to severe consequences, as can abrogation by the investigator to place the well-being of the subjects as the primary responsibility in any research protocol. Understanding how we arrived at the current approach and some of the failures that directed this course can support efforts to continually reevaluate and improve the safety of subjects who are willing to participate in research activities.