The Mississippi River, which drains 40% of the contiguous United States, functions as a transportation corridor, and a source of fresh water for residential and commercial purposes. All of these ecosystem services are affected by flooding, as was witnessed this spring as serious floods worked their way down the entire river system. In the past, individual flood events in the Midwest have incurred damages ranging from half a billion up to an estimated $20 billion, as many industrial and manufacturing facilities must shut down, residential and commercial properties are evacuated and damaged, and agricultural lands are flooded. Health risks continue after the floodwaters subside, as polluted water mixes with sewer overflows and other toxic materials, contaminating water supplies. Over the last few decades, the amount of precipitation and the frequency of heavy precipitation events have increased over the Midwestern United States. This trend is expected to continue in the future, as extreme precipitation events increase. Climate change is also expected to increase the amount of rain that falls in winter and spring, when frozen and/or saturated ground increases flood risk, while decreasing summer and fall rainfall. In this project, we used projections of future climate to estimate changes in the 100-year flood recurrence interval for communities along the Mississippi River between Herman, Missouri and Thebes, Illinois with a special focus on the St. Louis Region. We provide flood frequency analysis for three climate scenarios and three global climate models for the last 27 years, and future periods starting in 2010, 2040 and 2070. We also quantify the relative contribution of the Upper Mississippi and Missouri Rivers to flood discharges at St. Louis. Flood loss modeling was performed to assess the potential impacts of changes in the 100-year flood recurrence interval on future flood losses.