The cardiac ryanodine receptor (RyR) is the sarcoplasmic reticulum (SR) Ca-release channel which is centrally involved in the myocyte excitation–contraction (E–C) coupling process and certain cardiac arrhythmias, and even contributes to pacemaker activity in the heart. The RyR is also the center of a massive macromolecular complex which includes numerous regulatory proteins which can modulate RyR function. This complex includes proteins that interact with the cytoplasmic part of the RyR directly or indirectly (e.g. calmodulin (CaM), FK-506-binding proteins, protein kinase A, Ca–CaM-dependent protein kinase, phosphatases 1 and 2A, mAKAP, spinophilin, PR130, sorcin, triadin, junctin, calsequestrin and Homer). Information is evolving in terms of understanding both the physical/molecular nature of the protein–protein interactions between RyR and these other proteins. There is also a slowly developing picture as to how this complex of proteins may be involved in the functional modulation of the RyR. This RyR complex exists in physical proximity to regulatory complexes associated with sarcolemmal Ca channels, which have some similar components. These complexes, and their relative independence emphasizes the importance of thinking about other aspects of very local molecular signaling, analogous to the local control of SR Ca-release at the heart of current (E–C) coupling theory.