The 2001 U.S. Supreme Court's decision in Solid Waste Agency of Northern Cook County (SWANCC) held that isolated intrastate non-navigable waters could not be protected under the Clean Water Act (CWA) based on the presence of migratory birds. SWANCC represented a major reinterpretation of the CWA by re-emphasizing the importance of navigability in the definition of “waters of the United States” protected by the statute. The decision also implied that isolated waters might be “waters of the United States” where they had a “significant nexus” to navigable waters. Understanding the significance of SWANCC requires a historical look at the geographic scope of federal laws and regulations protecting surface waters. The concept of navigability had been prominent in the Rivers and Harbors Act of 1899, but the principal implementation focus for the CWA after its enactment in 1972 and prior to SWANCC had been on the hydrologic cycle and the relevance of links to interstate commerce for determining what waters were protected under the CWA. In upcoming years and months, the geographic jurisdiction of the CWA will continue to be debated in the courts, within Federal agencies, and by the public. Aquatic resource science will play a key role in helping ensure that the CWA is implemented in a scientifically defensible manner, consistent with SWANCC. One area in need of particular emphasis is additional research on the ways in which isolated waters help ensure the physical, chemical, and biological integrity of navigable waters and their tributaries. It is this question—the “significant nexus” between an intrastate non-navigable isolated water and the rest of the aquatic ecosystem—that will likely determine whether the water will be protected by the CWA.