Ryanodine receptors (RyRs)/Ca²⁺ release channels, on the endoplasmic and sarcoplasmic reticulum of most cell types, are required for intracellular Ca²⁺ release involved in diverse cellular functions, including muscle contraction and neurotransmitter release. The large cytoplasmic domain of the RyR serves as a scaffold for proteins that bind to and modulate the channel's function and that comprise a macromolecular signaling complex. These proteins include calstabins [FK506-binding proteins (FKBPs)], calmodulin (CaM), phosphodiesterase, kinases, phosphatases, and their cognate targeting proteins. This review focuses on recent progress in the understanding of RyR regulation and disease mechanisms that are associated with channel dysfunction.