The iconic Mississippi River is the lifeblood of the central United States. The River and working landscapes in which it is embedded provide essential goods and services for humanity that extend far beyond the borders of the United States. However, our use of these systems is creating a diverse array of sustainability challenges (water quantity and quality issues, land use change from urban expansion and biofuel development, forest and grassland fragmentation and biodiversity loss, declining social and human capital in rural and urban areas, etc. In addition, escalating climate change-related impacts are likely to exacerbate some of these challenges. Solving the sustainability challenges facing this system will require taking into account legacy effects from past management decisions, addressing cumulative synergistic impacts of current drivers, and building resilience and adaptive capacity to respond to future stresses. Developing more sustainable trajectories will require combining interdisciplinary scientific approaches that integrate the knowledge from the social and natural sciences with collaborative stakeholder efforts that gather knowledge from a diverse array of non-experts. We will discuss the role that the emerging field of sustainability science can serve in solving the challenges facing this system. This session in sponsored by new Center for Upper Mississippi River Studies at Augustana College in Rock Island, IL. Our goals are to: (1) Have participants discuss ongoing research projects; (2) Begin building a network of scientists and stakeholders working on sustainability issues; (3) Brainstorm ways the Center can serve as a hub and facilitate sustainability science endeavors in the system.