Detection of microvolt levels of T-wave alternans (TWA) has been shown to be useful in identifying individuals at heightened risk for sudden cardiac death. The mechanistic bases for TWA are complex, at the cellular level involving multiple mechanisms, particularly instabilities in membrane voltage (i.e., steep action potential duration restitution slope) and disruptions in intracellular calcium cycling dynamics. The integrative factors influencing TWA at the systemic level are also multifold. We focus on three main variables: heart rate, autonomic nervous system activity, and myocardial ischemia. Clinically, there is growing interest in extending TWA testing to include ambulatory ECG monitoring as well as exercise. The former modality permits assessment of the influence of diverse provocative stimuli of daily life, including physical activity, circadian factors, mental stress, and sleep-state related disturbances in respiratory and cardiovascular function. Two major emerging concepts in clinical TWA testing are discussed: quantitative analysis of TWA level to complement the current binary classification scheme, and risk stratification of patients with preserved left ventricular function, the population with the largest absolute number of sudden cardiac deaths.