The mechanisms underlying sudden cardiac death (SCD) are complex and diverse. Therefore, correct application of any marker to risk stratify patients for appropriate therapy requires knowledge regarding how the marker is reflective of a particular electroanatomical substrate for arrhythmias. Noninvasive measurement of beat-to-beat alternation of the electrocardiographic T-wave, referred to as T-wave alternans (TWA), is an important marker of risk for SCD. Is this relationship a mere association, or is TWA mechanistically linked to SCD? Recent experimental evidence strongly supports a mechanistic relationship between TWA and SCD. This review considers the underlying mechanisms of TWA derived from experimental studies, as they relate to clinical observations of TWA in humans, addressing the following questions derived from common clinical observations: (1) Where does TWA on the surface electrocardiogram come from? (2) Why is controlled heart rate elevation required to elicit TWA? (3) Why is TWA associated with risk for SCD? (4) Why is TWA associated with a broad range of ventricular arrhythmias? (5) How do commonly used medications affect TWA?