The chapter discusses the Extended-Hückel approach to calculating electronic coupling in biological electron transfer (ET) reactions. It highlights several recent observations that support the role of structured water molecules in enhancing ET rates between protein cofactors. Key findings include: 1. **Water-Mediated ET**: Studies by Winkler, Gray, Canters, Kliman, Onuchic, and others have shown that water molecules can significantly enhance intermolecular ET kinetics, often as effective as unimolecular ET over the same distance. 2. **Structured Water Coupling**: The structured water coupling regime is proposed as a crucial mechanism for facilitating ET reactions in the critical near-contact distance range relevant to biological ET kinetics. 3. **Influence of Protein Shape and Dynamics**: The influence of protein-protein shape complementarity, surface charge and polarity, and dynamical fluctuations on water-mediated coupling is explored. 4. **Multiple Tunneling Regimes**: The existence of multiple tunneling regimes, including unimolecular and water-mediated, is supported by recent experimental and theoretical observations. The chapter concludes by hypothesizing that water may be particularly effective as a tunneling mediator when it occupies sterically constrained spaces between redox cofactors, and suggests further investigation using both theoretical and experimental methods to understand how water-mediated coupling varies with protein properties and dynamics.The chapter discusses the Extended-Hückel approach to calculating electronic coupling in biological electron transfer (ET) reactions. It highlights several recent observations that support the role of structured water molecules in enhancing ET rates between protein cofactors. Key findings include: 1. **Water-Mediated ET**: Studies by Winkler, Gray, Canters, Kliman, Onuchic, and others have shown that water molecules can significantly enhance intermolecular ET kinetics, often as effective as unimolecular ET over the same distance. 2. **Structured Water Coupling**: The structured water coupling regime is proposed as a crucial mechanism for facilitating ET reactions in the critical near-contact distance range relevant to biological ET kinetics. 3. **Influence of Protein Shape and Dynamics**: The influence of protein-protein shape complementarity, surface charge and polarity, and dynamical fluctuations on water-mediated coupling is explored. 4. **Multiple Tunneling Regimes**: The existence of multiple tunneling regimes, including unimolecular and water-mediated, is supported by recent experimental and theoretical observations. The chapter concludes by hypothesizing that water may be particularly effective as a tunneling mediator when it occupies sterically constrained spaces between redox cofactors, and suggests further investigation using both theoretical and experimental methods to understand how water-mediated coupling varies with protein properties and dynamics.