Ion exchange (IEX) can successfully remove natural organic matter (NOM) from surface water. However, the removal mechanism is not well understood due to the complexity and variability of NOM in real source waters as well as the influence of multiple parameters on the removal behavior. For example, this includes the physicochemical properties of the NOM and IEX resin, and the presence of competing anions. Model compounds with a range of physical and chemical characteristics were therefore used to determine the mechanisms of NOM removal by IEX resins. Fifteen model compounds were selected to evaluate the influence of hydrophobicity, size, and charge of organic molecules on the removal by ion exchange, both individually and in mixtures. Three different resins, comprising polystyrene and polyacrylic resin of macroporous and gellular structure, showed that charge density (CD) was the most important characteristic that controlled the removal, with CD of >5 mequiv mgDOC-1 resulting in high removal (≥89%). Size exclusion of compounds with high MW (≥8 kDa) was evident. The hydrophobicity of the resin and model compound was particularly important for removal of neutral molecules such as resorcinol, which was best removed by the more hydrophobic polystyrene resin. Relationships were identified that provided explanations of the interactions observed between NOM and IEX resin in real waters.