Nonsedating H1-antihistamines are widely prescribed for the treatment of allergic disorders because of their lack of sedative and anticholinergic effects; however, certain nonsedating antihistamines such as terfenadine and astemizole are now known to cause QT prolongation and TdP, particularly in overdosage or with concomitant ingestion of imidazole antifungals or macrolide antibiotics. Mechanistic studies showed that the cardiotoxic effects of some nonsedating antihistamines are due to the inhibition of repolarization potassium channels, particularly IKr, which leads to prolongation of the action potential and QT interval, and the development of early after-depolarization, which triggers TdP. Patients at risk of developing TdP, such as those with congenital long QT syndrome, cardiac disease, liver disease, electrolyte disturbance, or those taking drugs that can prolong QT interval, should avoid nonsedating antihistamines that are also capable of prolonging the QT interval. Many questions still need to be answered, such as the role of other potassium channels (IKs, ITo, and Iped) and the relative expression of various potassium channels in different individuals, which may be important in the pathogenesis of TdP with nonsedating antihistamines. There is also a lack of information on the cardiac actions of newer nonsedating antihistamines. The evidence so far indicates that the potential to cause ventricular arrhythmias is not a class effect and that loratadine, cetirizine, and fexofenadine are not associated with QT prolongation, TdP, or other ventricular arrhythmias. It is hoped that with a better understanding of the arrhythmogenic mechanism of nonsedating antihistamines, we will be able to identify patients at risk and prevent any cardiac toxicity associated with H1-antihistamines, and ultimately, death.