In July 2012 President Obama signed the first ever National Strategy for Bio-surveillance that builds from existing capabilities and galvanizes U.S. efforts to identify and understand biological threats. Although focused on disease and pathogen surveillance in the continental U.S., the strategy recognizes the global importance of bio-surveillance. It is absolutely essential that nations are able to quickly detect and characterize a biological threat affecting human, animal, or agricultural health. This ability enables lives to be saved and improved outcomes in various scenarios, including purposeful release of a bio-threat agent, an emerging infectious disease outbreak, pandemic, environmental disaster, or food-borne illness. The ultimate goal of the U.S. bio-surveillance enterprise is the continuous collection and synergistic analysis of data from many disparate sources and the dissemination of actionable information followed by timely decision-making. This symposium discusses current U.S. and international disease surveillance approaches and the three critical challenges of improved diagnostics, predictive and epidemiological modeling, and data integration and analysis for decision support. Speakers will discuss the innovation and discovery needed to realize a successful bio-surveillance enterprise capable of capturing early warning signs and guiding public health decisions.