Intracellular calcium is a major coordinator of numerous aspects of cellular 
physiology, including muscle contractility and cell survival. In cardiac muscle, 
aberrant Ca(2+) cycling has been implicated in a range of pathological 
conditions including cardiomyopathies and heart failure. The sarco(endo)plasmic 
reticulum Ca(2+) transport adenosine triphosphatase (SERCA2a) and its regulator 
phospholamban (PLN) have a central role in modulating Ca(2+) homeostasis and, 
therefore, cardiac function. Herein, we discuss the mechanisms through which 
SERCA2a and PLN control cardiomyocyte function in health and disease. Emphasis 
is placed on our newly identified PLN-binding partner HS-1-associated protein 
X-1 (HAX-1), which has an anti-apoptotic function and presents with numerous 
similarities to Bcl-2. Recent evidence indicates that proteins of the Bcl-2 
family can influence ER Ca(2+) content, a critical determinant of cellular 
sensitivity to apoptosis. The discovery of the PLN/HAX-1 interaction therefore 
unveils an important new link between Ca(2+) homeostasis and cell survival, with 
significant therapeutic potential.