The Global Health Security Agenda (GHSA) describes a vision for a world that is safe and secure from infectious disease threats; it underscores the importance of developing the international capacity to prevent, detect, and respond to pandemic agents. In February 2014, the United States committed to support the GHSA by expanding and intensifying ongoing efforts across the US government. Implementing these goals will require interagency coordination and harmonization of diverse health security elements. Lessons learned from the Global Health Initiative (GHI), the President's Emergency Program for AIDS Relief (PEPFAR), and the Cooperative Threat Reduction (CTR) program underscore that centralized political, technical, and fiscal authority will be key to developing robust, sustainable, and integrated global health security efforts across the US government. In this article, we review the strengths and challenges of GHI, PEPFAR, and CTR and develop recommendations for implementing a unified US global health security program.