Regulating groundwater in the Eastern United States (U.S.), particularly transboundary aquifers between states, is a challenge given the patchwork quilt of common law, statutory frameworks, and agency rules. Such regulation is made more challenging by the need for better quantification of pumping and use. These dynamics are exemplified through several case studies, including the first ever U.S. Supreme Court case related to groundwater withdrawals (set in the Eastern U.S.). As dynamics such as expanded irrigation, population increases, and ecological considerations influence groundwater use across the Eastern U.S., water use will continue to be an important driver for economic activity and interaction within and between states. To effectively regulate transboundary aquifers, governance solutions must incorporate current science into decision making and be implemented at local, state, regional, and federal scales.