Ion channels, specialized pore-forming proteins, are an indispensable component of the nervous system and play a crucial role in regulating cardiac, skeletal, and smooth muscle contraction. Potassium ion channels, controlling the action potential of a number of excitable cells, are characterized by a remarkable ability to select K+ over Na+. Although the molecular basis for this striking ion selectivity has been a subject of extensive investigations using both experimental and theoretical methods, the following outstanding questions remain: (a) To what extent is the number of water molecules bound to the permeating ion (i.e., the hydration number) important for the K+/Na+ competition? (b) Are the chemical type and number of coordinating groups lining the pore critical for the selectivity process? (c) Apart from providing cation-ligating groups, do the channel walls play any other role in the selectivity process? This work reveals that the pore's selectivity for K+ over Na+ increases with (i) increasing hydration number of K+ relative to that of Na+, (ii) increasing number of K+-coordinating dipoles, (iii) increasing number of Na+-coordinating dipoles, and (iv) decreasing magnitude of the coordinating dipoles provided by the pore. Thus, a high K+/Na+ selectivity in K+ channels could be achieved from a combination of several favorable factors involving the native ion, the metal-coordinating ligands, and the protein matrix, viz., (a) an octahydrated permeating K+, (b) a pore lined with 8 carbonyl ligands, and (c) finely tuned physicomechanical properties of the channel walls providing a low dielectric medium favoring a high hydration number for the permeating K+ and enough stiffness to force the competing Na+ to adopt an unfavorable 8-fold coordination. This. implies that optimal K+/Na+ selectivity in K+ channels generally does not arise from solely structural or energetic consideration. The factors affecting ion selectivity revealed herein help to rationalize why valinomycin and the KcsA ion channels are highly K+-selective, whereas the NaK channel is nonselective. The calculations predict that other pores containing a different number/chemical type of coordinating groups from those observed in potassium channels could also select K+ over Na+.