Context: The International Health Regulations (IHR) have been the governing framework for global health security for the past decade and are a nearly universally recognized World Health Organization (WHO) treaty, with 196 States Parties. In the wake of the Ebola epidemic, major global commissions have cast doubt on the future effectiveness of the IHR and the leadership of the WHO.

Methods: We conducted a review of the historical origins of the IHR and their performance over the past 10 years and analyzed all of the ongoing reform panel efforts to provide a series of politically feasible recommendations for fundamental reform.

Findings: We propose a series of recommendations with realistic pathways for change. These recommendations focus on the development and strengthening of IHR core capacities; independently assessed metrics; new financing mechanisms; harmonization with the Global Health Security Agenda, Performance of Veterinary Services (PVS) Pathways, the Pandemic Influenza Preparedness Framework, and One Health strategies; public health and clinical workforce development; Emergency Committee transparency and governance; tiered public health emergency of international concern (PHEIC) processes; enhanced compliance mechanisms; and an enhanced role for civil society.

Conclusions: Empowering the WHO and realizing the IHR’s potential will shore up global health security—a vital investment in human and animal health—while reducing the vast economic consequences of the next global health emergency.