The standard in vitro method to assess the risk of drug-induced QT prolongation and arrhythmogenesis is the assessment of the inhibitory effect on the human Ether-a-go-go Related Gene (hERG) channel current. However, there are some drugs or group of drugs whose QT-prolonging and arrhythmogenic potency does not correlate with its inhibitory effect on the hERG channel. Recent studies suggest that analysis of drug effects on the voltage-dependence of channel activation and on the intracellular trafficking of the channel are also important for the evaluation of the arrhythmogenic risk of drugs. Combined use of voltage clamp and confocal microscopy enables such analysis and would provide insight into the mechanisms of drug-induced QT prolongation and arrhythmogenesis.