The skeletal muscle ryanodine receptor (RyR1) mediates excitation-contraction (E-C) coupling by facilitating the rapid release of Ca2+ from intracellular stores in the sarcoplasmic reticulum in response to activation of voltage gated Ca2+ channels residing in the T-tubule membrane. We have determined structures of rabbit RyR1 by cryogenic electron microscopy in open and closed conformations, and in the presence of multiple ligands and protein binding partners, providing insights into ryanodine receptor gating and regulation. Recent improvements in the local resolution of the first 3600 residues of the channel have allowed for the generation of an essentially complete atomic model of all ordered regions of the polypeptide chain, and the identification of novel ligand binding sites.