Emergency medicine research requires the enrollment of subjects with varying decision-making capacities, including capable adults, adults incapacitated by illness or injury, and children. These different categories of subjects are protected by multiple federal regulations. These include the federal Common Rule, the Department of Health and Human Services (DHHS) regulations for pediatric research, and the Food and Drug Administration's (FDA) Final Rule for the Exception from the Requirements of Informed Consent in Emergency Situations. Investigators should be familiar with the relevant federal research regulations to optimally protect vulnerable research subjects, and to facilitate the institutional review board (IRB) review process. IRB members face particular challenges in reviewing emergency research. No regulations exist for research enrolling incapacitated subjects using proxy consent. The wording of the Final Rule may not optimally protect vulnerable subjects. It is also difficult to apply conflicting regulations to a single study that enroll subjects with differing decision-making capacities. This article is intended as a guide for emergency researchers and IRB members who review emergency research. It reviews the elements of Federal Regulations that apply to consent, subject selection, privacy protection, and the analysis of risks and benefits in all emergency research. It explores the challenges for IRB review listed above, and offers potential solutions to these problems.