Over the course of more than a century, visible T-wave alternans (TWA), defined as a beat-to-beat alternation in the morphology and amplitude of the ST segment or T wave, has been observed to occur in close association with life-threatening arrhythmias in patients with acute myocardial ischemia and infarction, heart failure, Prinzmetal's angina, and channelopathies, including Brugada and long QT syndromes. Over 100 studies enrolling a total of more than 12,000 patients support the predictivity of TWA testing for cardiovascular mortality and sudden cardiac death during both exercise and ambulatory electrocardiogram monitoring. To date, the main intended application has been to aid decision-making for cardioverter-defibrillator implantation. The prospect that TWA could be used to guide pharmacologic therapy has not received adequate attention. The literature supporting the utility of TWA as a therapeutic marker of antiarrhythmic effects and proarrhythmia is reviewed for each of the major antiarrhythmic drug classes. Beta-adrenergic and sodium channel blocking agents are the most widely studied drug classes in clinical TWA investigations, which report reductions in TWA magnitude. Patients with Brugada syndrome constitute a significant exception, because sodium channel blockade provokes the diagnostic electrocardiogram changes as well as macroscopic TWA. Calcium channel blockers have undergone extensive research in several animal models, but, surprisingly, no clinical studies on TWA with this class of drugs have been performed. Interestingly, TWA may help to detect the beneficial effects of nonantiarrhythmic agents such as the angiotensin II receptor blocker valsartan, which exert their protective effects through putative indirect actions on myocardial remodeling. There is also suggestive evidence that the proarrhythmic effects associated with cardiovascular and noncardiovascular agents may be disclosed by elevated levels of TWA. Thus, the emerging collective evidence indicates the broad utility of TWA in estimating antiarrhythmic and proarrhythmic effects of diverse agents across differing pathologies. We conclude that quantitative analysis of TWA has considerable potential to guide pharmacologic therapy.