Institutional review boards (IRBs) or research ethics committees provide a core protection for human research participants through advance and periodic independent review of the ethical acceptability of proposals for human research. IRBs were codified in US regulation just over three decades ago and are widely required by law or regulation in jurisdictions globally. Since the inception of IRBs, the research landscape has grown and evolved, as has the system of IRB review and oversight. Evidence of inconsistencies in IRB review and in application of federal regulations has fueled dissatisfaction with the IRB system. Some complain that IRB review is time-consuming and burdensome without clear evidence of effectiveness at protecting human subjects. Multiple proposals have been offered to reform or update the current IRB system, and many alternative models are currently being tried. Current focus on centralizing and sharing reviews requires more attention and evidence. Proposed changes to the US federal regulations may bring more changes. Data and resourcefulness are needed to further develop and test review and oversight models that provide adequate and respectful protections of participant rights and welfare and that are appropriate, efficient, and adaptable for current and future research.