Muscle excitation-contraction coupling is, in large part, regulated by the activity of two proteins. These are the ryanodine receptor (RyR), which is an intracellular Ca²⁺ release channel and the dihydropyridine receptor (DHPR), which is a voltage gated L-type calcium channel. In skeletal muscle, the physical association between RyR1 and L-type Ca²⁺ channels is required for muscle excitation-contraction coupling. RyRs also regulate intracellular Ca²⁺ homeostasis, thereby contributing to a variety of cellular functions in different tissues. A wide variety of modulators directly regulate RyR1 activity and, consequentially, alter both excitation-contraction coupling and calcium homeostasis. Calmodulin, one of these cellular modulators, is a ubiquitously expressed 17 kDa Ca²⁺ binding protein containing four E-F hands, which binds to RyR1 at both nanomolar and micromolar Ca²⁺ concentrations. Apocalmodulin (Ca²⁺ free calmodulin) is a partial agonist, while Ca²⁺calmodulin is an inhibitor of RyR1. This conversion of calmodulin from an activator to an inhibitor is due to Ca²⁺ binding to the two C-terminal sites on calmodulin. Calmodulin can also modulate the L-type Ca²⁺ channel in the transverse tubule membrane, producing either inactivation or facilitation of the channel upon elevation of the local Ca²⁺ concentrations. Calmodulin binds to a region on RyR1 corresponding to amino acids 3614-3643 and to a region in the carboxy-terminal tail of the L-type Ca²⁺ channel α₁ subunit. However, these calmodulin binding motifs on both proteins bind to undetermined motifs on the other protein, suggesting that they represent more general protein-protein interaction motifs. These findings raise questions about the role of calmodulin in excitation-contraction coupling in skeletal muscle.