Under the current US Department of Health and Human Services regulatory and ethical system for research involving human subjects, research is defined in terms of several key concepts: intent, systematic investigation, and generalizability. If an investigator engages in a systematic investigation designed or intended to contribute to generalizable knowledge, then he or she is engaged in research. If that research involves living individuals and the investigator will either interact or intervene with people or obtain their identifiable personal information, then the research must be prospectively reviewed by an institutional review board (IRB), a federally mandated committee that ensures the ethical and regulatory appropriateness of proposed research. In public health institutions, and especially at state departments of health, this definition of research may prove vexing for determining when particular public health activities must be reviewed by IRBs. This article outlines several reasons for such vexation and 2 key responses from major public health stakeholders. In the current climate of public health preparedness initiatives at state health departments for disasters and bioterrorism, how research is defined vis-à-vis public health interventions may add even more confusion to preparedness initiatives and pose difficulties in determining when IRB review and the added protections it affords are appropriate. This article suggests several practical ways to avoid confusion and attempts to strike a balance between the need for expeditious approvals of research-based responses to public health disasters and to ensure proper protections for human subjects at state health departments. It is hoped that these suggestions can assist not only state health departments but also academically based researchers who either collaborate with those departments or whose research will need to be reviewed by their IRBs.