This document provides guidance to investigators and managers associated with the U.S. Environmental Protection Agency (EPA) Office of Research and Development's (ORDs) National Exposure Research Laboratory (NERL) on the ethical conduct, regulatory review, and approval of all human research activities. The focus of this document is twofold: first, on the methods for ensuring the safety and rights of human research subjects; and, second, on how to conduct such research in a manner consistent with EPA and NERL policy. Principal investigators (PIs) are responsible for obtaining approval for human subjects research. If a PI does not have significant experience in the approval process for human subjects research, he or she should rely on an experienced colleague or co-investigator (Co-I) or contact the Office of the Director of the Human Research Protocol Office (HRPO) located at the National Health and Environmental Effects Research Laboratory Human Studies Facility in Chapel Hill, NC. The mission of the HRPO is to assist investigators in all aspects of the ethical and regulatory review of human subjects research.