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(+).