We sought to determine whether extracellular Ca²⁺ (Ca _e ²⁺ ) and K⁺ (K _e ⁺ ) play essential roles in the normal functioning of cardiac K⁺ channels. Reports by others have shown that removal of Ca _e ²⁺ and K _e ⁺ alters the gating properties of neural delayed rectifier (I _K) and A-type K⁺ currents, resulting in a loss of normal cation selectivity and voltage-dependent gating. We found that removal of Ca _e ²⁺ and K _e ⁺ from the solution bathing guinea pig ventricular myocytes often induced a leak conductance, but did not affect the ionic selectivity or time-dependent activation and deactivation properties of I _K. The effect of [K⁺]_e on the magnitude of the two components of cardiac I _K was also examined. I _K in guinea pig myocytes is comprised of two distinct types of currents: I _Kr (rapidly activating, rectifying) and I _Ks (slowly activating). The differential effect of Ca _e ²⁺ on the two components of I _K (previously shown to shift the voltage dependence of activation of the two currents in opposite directions) was exploited to determine the role of K _e ⁺ on the magnitude of I _Ks and I _Kr. Lowering [K⁺]_e from 4 to 0 mM increased I _Ks, as expected from the change in driving force for K⁺, but decreased I _Kr. The differential effect of [K⁺]_e on the two components of cardiac I _K may explain the reported discrepancies regarding modulation of cardiac I _K conductance by this cation.