Ryanodine receptors (RyRs) are the largest known ion channels. They are Ca2+ release channels found primarily on the sarcoplasmic reticulum of myocytes. Several hundred mutations in RyRs are associated with skeletal or cardiomyocyte disease in humans. Many of these mutations can now be mapped onto the high resolution structures of individual RyR domains and on full‐length tetrameric cryo‐electron microscopy structures. A closely related Ca2+ release channel, the inositol 1,4,5‐trisphospate receptor (IP3R), shows a conserved structural architecture at the N‐terminus, suggesting that both channels evolved from an ancestral unicellular RyR/IP3R. The functional insights provided by recent structural studies for both channels will aid in the development of rationale treatments for a myriad of Ca2+‐signaled malignancies.