Signaling between cell membrane-bound L-type Ca²⁺ channels (LTCC) and ryanodine receptor Ca²⁺ release channels (RyR) on sarcoplasmic reticulum (SR) stores grades excitation–contraction coupling (ECC) in striated muscle. A physical connection regulates LTCC and RyR in skeletal muscle, but the molecular mechanism for coordinating LTCC and RyR in cardiomyocytes, where this physical link is absent, is unknown. Calmodulin kinase (CaMK) has characteristics suitable for an ECC coordinating molecule: it is activated by Ca²⁺/calmodulin, it regulates LTCC and RyR, and it is enriched in the vicinity of LTCC and RyR. Intact cardiomyocytes were studied under conditions where CaMK activity could be controlled independently of intracellular Ca²⁺ by using an engineered Ca²⁺-independent form of CaMK and a highly specific CaMK inhibitory peptide. CaMK reciprocally enhanced L-type Ca²⁺ current and reduced release of Ca²⁺ from the SR while increasing SR Ca²⁺ content. These findings support the hypothesis that CaMK is required to functionally couple LTCC and RyR during cardiac ECC.