The cation-π interaction is a significant noncovalent force in molecular recognition, alongside the hydrophobic effect, hydrogen bonds, and ion pairs. This Account provides insights into the origins and nature of the cation-π interaction. Early studies on cyclophanes showed that cationic molecules prefer hydrophobic environments over aqueous ones when lined with π systems. Gas-phase studies revealed the strength of cation-π interactions, with Li⁺ binding benzene with 38 kcal/mol and NH₄⁺ with 19 kcal/mol. These interactions are stronger than polar-π interactions. Cation-π interactions are energetically significant in aqueous and biological systems, enhancing binding energies by 2–5 kcal/mol, making them competitive with hydrogen bonds and ion pairs. The cation-π interaction includes an electrostatic component, with benzene's C-H bond dipoles creating a negative electrostatic potential. The binding strength decreases with larger ions, following a classical electrostatic trend. Polarizability does not define these interactions, as cyclohexane is more polarizable than benzene but a poorer cation binder. Cation-π interactions are observed in protein structures, particularly with lysine and arginine side chains interacting with aromatic residues. These interactions are crucial in neurotransmitter binding, drug-receptor interactions, and biological processes like the binding of nicotine to ACh receptors. Studies on cyclophanes and unnatural amino acids have shown that cation-π interactions are vital in neurobiology. The cation-π interaction was first described by Kebarle, and later named by Dougherty. It is now recognized as a key factor in molecular recognition and catalysis. Cation-π interactions are prevalent in biological systems, with over 500,000 interactions in the PDB. They are especially important in protein-protein interfaces and in the binding of small molecules like glycine. Cation-π interactions are not limited to quaternary ammonium ions but also involve other cations such as Na⁺, K⁺, and metal ions. These interactions are crucial in various biological processes, including the recognition of the histone code, terpene biosynthesis, and chemical catalysis. The aromatic box motif, found in proteins like ACh receptors, highlights the importance of cation-π interactions in binding. These interactions are also critical in plant photoreceptors and in the function of ion channels. The cation-π interaction is a fundamental force in chemistry and biology, influencing molecular recognition, catalysis, and biological processes. Its significance is supported by extensive experimental and theoretical studies, demonstrating its role in drug-receptor interactions, protein structure, and biological function.The cation-π interaction is a significant noncovalent force in molecular recognition, alongside the hydrophobic effect, hydrogen bonds, and ion pairs. This Account provides insights into the origins and nature of the cation-π interaction. Early studies on cyclophanes showed that cationic molecules prefer hydrophobic environments over aqueous ones when lined with π systems. Gas-phase studies revealed the strength of cation-π interactions, with Li⁺ binding benzene with 38 kcal/mol and NH₄⁺ with 19 kcal/mol. These interactions are stronger than polar-π interactions. Cation-π interactions are energetically significant in aqueous and biological systems, enhancing binding energies by 2–5 kcal/mol, making them competitive with hydrogen bonds and ion pairs. The cation-π interaction includes an electrostatic component, with benzene's C-H bond dipoles creating a negative electrostatic potential. The binding strength decreases with larger ions, following a classical electrostatic trend. Polarizability does not define these interactions, as cyclohexane is more polarizable than benzene but a poorer cation binder. Cation-π interactions are observed in protein structures, particularly with lysine and arginine side chains interacting with aromatic residues. These interactions are crucial in neurotransmitter binding, drug-receptor interactions, and biological processes like the binding of nicotine to ACh receptors. Studies on cyclophanes and unnatural amino acids have shown that cation-π interactions are vital in neurobiology. The cation-π interaction was first described by Kebarle, and later named by Dougherty. It is now recognized as a key factor in molecular recognition and catalysis. Cation-π interactions are prevalent in biological systems, with over 500,000 interactions in the PDB. They are especially important in protein-protein interfaces and in the binding of small molecules like glycine. Cation-π interactions are not limited to quaternary ammonium ions but also involve other cations such as Na⁺, K⁺, and metal ions. These interactions are crucial in various biological processes, including the recognition of the histone code, terpene biosynthesis, and chemical catalysis. The aromatic box motif, found in proteins like ACh receptors, highlights the importance of cation-π interactions in binding. These interactions are also critical in plant photoreceptors and in the function of ion channels. The cation-π interaction is a fundamental force in chemistry and biology, influencing molecular recognition, catalysis, and biological processes. Its significance is supported by extensive experimental and theoretical studies, demonstrating its role in drug-receptor interactions, protein structure, and biological function.