Regulatory bodies and institutional review boards are increasingly considering human subjects who are vulnerable to research not because of their intrinsic characteristics, but because of the particular situations or circumstances that they bring with them as potential research participants. Several subsets of emergency department patients may be considered vulnerable in the research setting. This may include patients who are vulnerable because of a medical condition, a baseline limitation of intellectual function, a social setting, psychosocial stressors, or other factors. These issues should be carefully considered when including such patients in research protocols. Special efforts should be made to ensure voluntary participation and understanding of the purposes and risks of participation.