Calmodulin and the Philosopher's Stone. It has been recognized for some time that intracellular Ca2+ ([Ca2+]i) can contribute to the genesis of cardiac arrhythmias, but understanding of the molecular signaling machinery that links disordered [Ca2+]i to arrhythmias has been lacking. Exciting recent work has focused on the ubiquitous intracellular Ca2+-binding protein calmodulin. Calmodulin is a molecular sensor that can translate increases in [Ca2+]i into modulatory signals for ion channels and activate other Ca2+-dependent signaling molecules. This article will examine the implications of these recent findings for arrhythmogenesis and the development of new antiarrhythmic therapies.