It has been said that large rivers are the bloodlines of continents, and the Mississippi River system is the most prominent bloodline in North America. The Mississippi drainage stretches from the Rocky Mountains in the western USA to the Appalachian Cordillera in the east, and sediment from this vast area is then routed to the alluvial–deltaic plain of south Louisiana and the basin-floor fan in the deep Gulf of Mexico (GoM). Origins of the Mississippi system can be traced to the Late Cretaceous–Early Paleocene reorganization of North American drainage. However, integration of a continental-scale Mississippi drainage is a Late Neogene phenomenon, and sediment routing to the GoM has changed significantly over multiple timescales in response to a variety of large-scale natural forcing mechanisms and to human activities. This paper reviews large-scale change in drainage, sediment routing and sediment storage for the Mississippi system over timescales of 150 myr, where tectonic and geodynamic processes dominate, the last 150 kyr, where Milankovitch climate and sea-level changes dominate, and the 150 year period of the twentieth and twenty-first centuries when human activities have fundamentally altered the sediment routing and dispersal system.