The Trump administration has proposed replacing the Clean Water Rule, a 2015 regulation that defined the statutory term "waters ofthe United States" to clarify the geographic jurisdiction of the Clean Water Act. Since its promulgation, the Clean Water Rule has been subjected to numerous judicial challenges. We submitted an amici curiae brief to the United States Court of Appeals for the Sixth Circuit, explaining why the Clean Water Rule, and its definition of "waters of the United States," is scientifically sound. The definition of "waters of the United States" is a legal determination informed by science. The best available science supports the Clean Water Rule’s categorical treatment of tributaries because compelling scientific evidence demonstrates that tributaries significantly affect the chemical, physical, and biological integrity of traditional navigable waters (primary waters). Similarly, the best available science supports the Clean Water Rule’s categorical treatment of adjacent waters based on geographic proximity. Compelling scientific evidence demonstrates that waters within 100 ft of an ordinary high water mark (OHWM) significantly affect the chemical, physical, and biological integrity of primary waters, as do waters within 100-year floodplains and waters within 1500 ft of high tide lines of tidally influenced primary waters or OHWMs of the Great Lakes. This review article is adapted from that amici brief.