Separation materials that can isolate single solutes from multi-solute solutions are essential for resource recovery and contaminant removal during water purification processes. The model benchmark for synthetic membrane design is the biological K + channel, which can achieve a selectivity ratio of 1000 K + to 1 Na + . Inspiration from the selectivity of natural ion channels has led to a focus on the development of several classes of materials, such as polymeric membranes, MOFs, 2D graphene and graphene oxides, and carbon nanotubes. These materials offer a high degree of tunability via chemical functionalization, allowing for simultaneous control of pore geometry and surface chemistry to, in principle, achieve high ion selectivity and permeability necessary for membrane design. Numerous investigations have been conducted to identify the structural and molecular features that contribute to this performance, which provide guidance for the continued development of synthetic membranes with high selectivity. Investigations of ion selectivity in K + channels in the last 20 years have identified structural rigidity, coordination number, ligand field strength, among others features, as key determinants of selectivity. For synthetic membranes, experimental and computational studies have shown that the solute binding energy to polymeric membrane channels is a predictor of permeability. Furthermore, multi-solute selectivity has been shown to be governed by differences in barrier heights (i.e., by invoking transition state theory) of each unique species of solute as it diffuses through a channel. These energy barriers are controlled by molecular-scale features, e.g., the strength of interaction between solute and pore walls, material pore size, solute and material electrostatics, as well as bulk properties such as the dielectric constant. Therefore, determining the binding energies associated with multiple ion species with multiple coordinating environments is needed to understand how to design materials for selectivity.