Cytosolic free [Ca2+] ([Ca2+]c) mediates primary regulation of cardiac contractility. Both the magnitude and time-course of [Ca2+]c transient that is elicited by a sarcolemmal action potential play central roles in defining the characteristics of the mechanical response that occurs during a single excitation-contraction coupling cycle. Numerous modulators of cardiac contractility, both hormonal and autoregulatory, act to influence contractile function via direct effects on various cellular processes that govern [Ca2+]c dynamics. Cardiac contractility can also be influenced by mechanisms that alter the responsiveness of the contractile element to activation by Ca2+ (see preceding paper). There is growing interest in the possibility that the phosphorylation of the P-light chain subunit of cardiac myosin by a Ca(2+)-calmodulin-dependent myosin light chain kinase may modulate cardiac muscle contractility by increasing the sensitivity of the contractile element to activation by Ca2+. The types of experimental data that have led to the development of this hypothesis and the unique aspects of cardiac P-light chain phosphate content regulation will be briefly addressed in this paper. Furthermore, several unresolved issues regarding the functional significance of cardiac P-light chain phosphorylation in intact myocardium are identified.