Molybdenum-99 (Mo-99) is used in the production of technetium-99m, the most commonly used medical radioisotope in the world. Because the U.S. lacks a domestic production capability, its demand is met by other countries, whose processes have recently proven unreliable. In addition, the foreign producers utilize highly enriched uranium (HEU), a practice contrary to the National Nuclear Security Administration's (NNSA) Nuclear Security Goal to minimize the use of HEU in civilian applications. As a part of the Global Threat Reduction Initiative's Mo-99 Program, in Fiscal Years 2009 and 2010, NNSA entered into cooperative agreements (CA) with four commercial entities to accelerate the domestic production of Mo-99 without the use of HEU. Progress has been made in developing a reliable domestic production capability for Mo-99. For example, our review disclosed that as of January 2012, the CA partners had met established milestones. Although one of the partners has indefinitely suspended operations and a second is not expected to meet the 2014 deadline, NNSA officials told us that program objectives can still be achieved by the remaining partners. Further, our tests did not reveal any material internal control weaknesses in selected areas of CA administration. Finally, while there are significant challenges to establishing a reliable domestic production capability for Mo-99, NNSA is aware of the challenges and is considering how best to address them. Therefore, we made suggestions to management for ensuring compliance with the respective CAs and developing viable mitigation strategies for the challenges.