The development of an efficient and economical system for extracting uranium from seawater could lead to an essentially limitless source of fuel for nuclear reactors. Currently, the most promising technology for recovering uranium from seawater involves the use of polymeric sorbents functionalized with the amidoxime moiety. However, competition of amidoxime sorbents with carbonate for uranium, indiscriminate sorption of other seawater cations, seawater temperature, and sorbent durability affect the efficiency and cost of this technology. Insights from thermodynamic and structural studies have proved to be powerful tools for addressing these issues and aiding the development of more effective sorbents for uranium. We summarize herein the results of these studies and discuss their implications for the extraction of uranium from seawater.