Drug induced Long QT syndrome results primarily from block of the cardiac potassium channel heRG (human-ether-a-gogo related gene). In some cases prolongation of the QT interval can result in the lethal arrhythmia torsade de pointes, an arrhythmia characterized by a rapid heart rate and severely compromised cardiac output. Many patients requiring medication present with abnormal serum electrolyte levels due to a variety of conditions including gastrointestinal dysfunction, renal and endocrine disorders, diuretic use, alcoholism and aging. Extracellular cations have significant influence on HERG channel gating and in some instances they have been shown to alter drug block of heRG. however, the mechanisms by which drug block is altered in different extracellular cation solutions are not well understood. In this study, heRG block by quinidine and cisapride was assessed in extracellular solutions of calcium, potassium, rubidium, cesium and tetraethylammonium (TeA) using two-electrode voltage clamping of Xenopus oocytes. Consistent with previous reports we show that increases in extracellular potassium reduce heRG block by quinidine and cisapride. We also show that increasing extracellular rubidium and cesium reduced heRG block by quinidine and cisapride whereas increasing extracellular calcium and extracellular TeA did not alter heRG block by quinidine and cisapride. These results demonstrate that at lower extracellular potassium concentrations, the permeant ion is almost exclusively responsible for the reduction in quinidine and cisapride block of heRG due to increases in extracellular potassium.