The Na-K-ATPase is an energy-transducing ion pump that converts the free energy of ATP into transmembrane ion gradients. It also serves as a functional receptor for cardiotonic steroids such as ouabain and digoxin. Binding of ouabain to the Na-K-ATPase can activate calcium signaling in a cell-specific manner. The exquisite calcium modulation via the Na-K-ATPase is achieved by the ability of the pump to integrate signals from numerous protein and non-protein molecules, including ion transporters, channels, protein kinases/phosphatases, as well as cellular Na+. This review focuses on the unique properties of the Na-K-ATPase and its role in the formation of different calcium-signaling microdomains.