The sodium-potassium pump is widely recognized as the principal mechanism for active ion transport across the cellular membrane of cardiac tissue, being responsible for the creation and maintenance of the transarcolemmal sodium and potassium gradients, crucial for cardiac cell electrophysiology. Importantly, sodium-potassium pump activity is impaired in a number of major diseased conditions, including ischemia and heart failure. However, its subtle ways of action on cardiac electrophysiology, both directly through its electrogenic nature and indirectly via the regulation of cell homeostasis, make it hard to predict the electrophysiological consequences of reduced sodium-potassium pump activity in cardiac repolarization. In this review, we discuss how recent studies adopting the systems biology approach, through the integration of experimental and modeling methodologies, have identified the sodium-potassium pump as one of the most important ionic mechanisms in regulating key properties of cardiac repolarization and its rate dependence, from subcellular to whole organ levels. These include the role of the pump in the biphasic modulation of cellular repolarization and refractoriness, the rate control of intracellular sodium and calcium dynamics and therefore of the adaptation of repolarization to changes in heart rate, as well as its importance in regulating pro-arrhythmic substrates through modulation of dispersion of repolarization and restitution. Theoretical findings are consistent across a variety of cell types and species including human, and widely in agreement with experimental findings. The novel insights and hypotheses on the role of the pump in cardiac electrophysiology obtained through this integrative approach could eventually lead to novel therapeutic and diagnostic strategies. © 2013 Springer-Verlag Berlin Heidelberg.