Na(+) , K(+) -ATPase (NKA) is well known for its function as an ion pump. Studies during the last decade have revealed an additional role for NKA as a signal transducer. In this brief review we describe how cardiotonic steroids (CTS), which are highly specific NKA ligands, trigger slow Ca(2+) oscillations by promoting the interaction between NKA and IP3R, and how this Ca(2+) signal activates the NF-κB subunit p65 and increases the expression of the anti-apoptotic factor Bcl-xL. The potential tissue protective effects of this signal are discussed. This article is protected by copyright. All rights reserved.