The Laurentian Great Lakes are vast, spatially heterogeneous, and changing. Across these hydrologically linked basins, some conditions approach biogeochemical extremes for freshwater systems anywhere. Some of the biogeochemical processes operate over nearly as broad a range of temporal and spatial scales as is possible to observe in freshwater. What we know about the biogeochemistry of this system is strongly influenced by an intense focus on phosphorus loading, eutrophication, and partial recovery; therefore, some important biogeochemical processes are known in detail while others are scarcely described. These lakes serve as a life support system for tens of millions of people, and they generate trillions of dollars of economic activity. Many biogeochemical changes that have occurred have surprised us. Biogeochemistry affects how these lakes perform these functions and should be a higher research priority. ▪ The biogeochemical functioning of the Great Lakes affects tens of millions of people and trillions of dollars of economy, but our knowledge of their biogeochemistry is fragmentary. ▪ The history of environmental damage and recovery in the Great Lakes is long and includes many surprises. ▪ Large lakes such as the Great Lakes combine characteristics of small lakes and the world's oceans, making them worthy objects of study to advance fundamental understanding. ▪ The Great Lakes are understudied relative to their scale and importance. Expected final online publication date for the Annual Review of Earth and Planetary Sciences, Volume 49 is May 28, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.