Electrocardiographic alternans, a phenomenon of beat-to-beat alternation in cardiac electrical waveforms, has been implicated in the pathogenesis of ventricular arrhythmias and sudden cardiac death (SCD). In the clinical setting, a positive microvolt T-wave alternans test has been associated with a heightened risk of arrhythmic mortality and SCD during medium- and long-term follow-up. However, rather than merely being associated with an increased risk for SCD, several lines of preclinical and clinical evidence suggest that cardiac alternans may play a causative role in generating the acute electrophysiological substrate necessary for the onset of ventricular arrhythmias. Deficiencies in Ca²⁺ transport processes have been implicated in the genesis of alternans at the subcellular and cellular level and are hypothesized to contribute to the conditions necessary for dispersion of refractoriness, wave break, reentry, and onset of arrhythmia. As such, detecting acute surges in alternans may provide a mechanism for predicting the impending onset of arrhythmia and opens the door to delivering upstream antiarrhythmic therapies. In this review, we discuss the preclinical and clinical evidence to support a causative association between alternans and acute arrhythmogenesis and outline the potential clinical implications of such an association.