The Indus River Basin is characterized by downstream areas with the world's largest irrigation system, providing food and energy security to more than 215 million people. The arid to semiarid basin is classified as a net water deficit area, but it also suffers from devastating floods. Among the four basin countries, Pakistan is most dependent on water originating in high mountain catchments and is therefore most vulnerable to climatic, socioeconomic, and other global changes that are impacting both supply and demand. Given the consensus that there is a lack of systematic and consistent hydrological, meteorological, biophysical, and socioeconomic data to promote integrated water resources management (IWRM) at the basin scale, an international consultation of scientists, water managers, and development partners was organized in 2010. These experts suggested developing a long-term Indus Basin Research Program aiming to build a robust, consolidated, and shared scientific knowledge base and thus improve understanding of the coupled human and ecological processes and their interrelationships in the basin. This paper summarizes the rationale for initiating such a coordinated multidisciplinary research, knowledge management, and capacity development process aiming to support water management policies and programs from design stage to implementation, using the framework of integrated river basin management (IRBM). The paper further stresses the need to implement IRBM using IWRM tools, recognizing that multiple factors and actors play critical roles in improving management of water and other natural resources to enhance overall water productivity. The steps needed to initiate and consolidate national and international institutional coordination, capacity development, and policy support to operationalize an IRBM process are spelled out. A long-term research and capacity-building program for international organizations and scientists is recommended to foster transboundary cooperation and scientific collaboration.