RyRs are large homotetrameric proteins that are approximately 4/5 cytoplasmic and approximately 1/5 transmembrane and luminal in mass. Mutations in RyRs produce human disease and many of these disease-causing mutations are in the cytoplasmic domains. To elucidate the mechanisms of a disease and to develop interventions, it is crucial to determine how the alterations in the cytoplasmic domains communicate with the transmembrane pore of this channel. One of the major activators of all three RyR isoforms is Ca2+ and some of the disease-causing mutations are thought to alter the sensitivity of the channels to Ca2+ activation. This review examines the current state of structural understanding of the RyR channel activation.