L. S. Maier and D. M. Bers. Calcium, Calmodulin, and Calcium-Calmodulin Kinase II: Heartbeat to Heartbeat and Beyond. Journal of Molecular and Cellular Cardiology (2002) 34, 919–939. Calcium (Ca) is the key regulator of cardiac contraction during excitation–contraction (E–C) coupling. However, differences exist between the amount of Ca being transported into the myocytes upon electrical stimulation as compared to Ca released from the sarcoplasmic reticulum (SR). Moreover, alterations in E–C coupling occur in cardiac hypertrophy and heart failure. In addition to the direct effects of Ca on the myofilaments, Ca plays a pivotal role in activation of a number of Ca-dependent proteins or second messengers, which can modulate E–C coupling. Of these proteins, calmodulin (CaM) and Ca-CaM-dependent kinase II (CaMKII) are of special interest in the heart because of their role of modulating Ca influx, SR Ca release, and SR Ca uptake during E–C coupling. Indeed, CaM and CaMKII may be associated with some ion channels and Ca transporters and both can modulate acute cellular Ca handling. In addition to the changes in Ca, CaM and CaMKII signals from beat-to-beat, changes may occur on a longer time scale. These may occur over seconds to minutes involving phosphorylation/dephosphorylation reactions, and even a longer time frame in altering gene transcription (excitation–transcription (E–T) coupling) in hypertrophic signaling and heart failure. Here we review the classical role of Ca in E–C coupling and extend this view to the role of the Ca-dependent proteins CaM and CaMKII in modulating E–C coupling and their contribution to E–T coupling.