Editors' Summary: This Article presents an argument that EPA's use of reference concentrations (RfCs) in risk assessments, if upheld by the courts, will dramatically change the nature of health-based regulation. In a background section, the Article summarizes RfC methodology and its origins. The Article compares the traditional standard-setting approach, in which the Agency first identifies a level of exposure that presents a significant risk of harm and then sets a standard below that level, with EPA's RfC-based approach, which allows the Agency to avoid identifying an exposure level that poses a significant risk. Next, using EPA's regulatory decisions about manganese as a case study, the Article illustrates EPA's use of the methodology in risk assessment. In a discussion and analysis section, the Article focuses on how RfCs can be used to manipulate risk-assessment results, and reviews the courts' reaction to the methodology to date. The Article then recommends that members of the regulated community oppose RfC-based risk-assessment methodology in judicial and legislative forums. The Article concludes that EPA's use of the methodology reflects a move toward a zero-risk regulatory paradigm and is a questionable attempt to assign to the regulated community the burden of disproving the existence of any theoretically possible risk to public health.