Reducing the use of highly enriched uranium (HEU) can lower the likelihood of adversaries obtaining a nuclear material that can be used in an improvised nuclear explosive. With this objective in mind, Congress directed the Department of Energy to request a study from the National Academies on the elimination of HEU in reactor fuel, reactor targets, and medical isotope production facilities. The report addresses the feasibility of procuring supplies of medical isotopes from sources that do not use HEU, current and projected demand and availability of medical isotope production, and the potential cost differentials between different methods of production.