Ryanodine receptors (RyRs) are massive intracellular Ca2+ channels that generate large intracellular Ca2+ signals in myocytes, neurons, and other cell types. RyR channels, membrane proteins in the endoplasmic reticulum, are subject to complex regulation. Cryo-electron microscopy (cryo-EM) saw a major leap in resolution around 2016, when direct detectors combined with computational advances enabled near-atomic structures of proteins. Since then, unique cryo-EM structures of RyR in various states provide a structural framework for a wealth of existing functional data. These structures reveal an ultra-complex machinery assembled from diverse domains, including helical repeats, SPRY domains, EF hands, and zinc fingers, which form binding sites for multiple ligands. This chapter focuses on the conformational changes RyRs undergo in response to physiological effectors. Ca2+ and Mg2+ command activation, inhibition, and inactivation. CaM acts as a mobile subunit that changes domain connectivity according to Ca2+ concentration. FKBP props up the cytoplasmic shell and coordinates the four subunits. Single-point disease-causing mutations have a profound impact on long-range allostery, which, for RyR1, can be partially reversed by dantrolene, an FDA-approved drug. The integration of structural and functional knowledge provides a quintessential example of allostery, which is useful in the research of other proteins and offers valuable guidance to design new therapies.