T-wave alternans (TWA) reflects beat-to-beat fluctuations in the electrocardiographic T-wave, and is associated with dispersion of repolarization and the mechanisms for sudden cardiac arrest (SCA). This review examines the bench-to-bedside literature that, over decades, has linked alternans of repolarization in cellular, whole-heart, and human studies with spatial dispersion of repolarization, alternans of cellular action potential, and fluctuations in ionic currents that may lead to ventricular arrhythmias. Collectively, these studies provide a foundation for the clinical use of TWA to reflect susceptibility to ventricular arrhythmias in several disease states. This review then provides a contemporary evidence-based framework for the use of TWA to enhance risk stratification for SCA, identifying populations for whom TWA is best established, those for whom further studies are required, and areas for additional investigation.