Despite the large number of available antiarrhythmic agents, significant QT-interval prolongation and risk of severe proarrhythmia, including torsade de pointes, limit pharmacological opportunities in the management of atrial arrhythmias. The risk of proarrhythmia has been demonstrated in class I and class III drugs, but significant variability has been observed between agents of the same class. Electrophysiological drug effects found to be important in the etiology of proarrhythmia include QT-interval prolongation through selective blockade of the delayed rectifying potassium current (I(Kr)), early afterdepolarizations, transmural dispersion of repolarization, and a reverse rate dependence. Interestingly, less proarrhythmic potential is seen or anticipated with agents that are able to block multiple ion channels and those with atrial selectivity, despite moderate QT prolongation. This observation has helped steer the development of newer drugs, with some promising preliminary results.