This review focuses on role played by two modulators of ryanodine receptors (RyRs), one a small molecule (1,4‐benzothiazepine) and the other a protein subunit of the channel (FKBP or calstabin), both of which exert potent effects on the channel. These regulators of the RyR channels have potential therapeutic implications in that the small molecule and the protein have novel anti‐arrhythmic and anti‐heart failure activities involving the cardiac (RyR2) and skeletal (RyR1) ryanodine receptors. Protein kinase A (PKA) hyperphosphorylation of RyR2 in failing hearts or mutations in RyR2 linked to sudden cardiac death (SCD) can result in diastolic sarcoplasmic reticulum (SR) Ca²⁺ leak that can trigger fatal cardiac arrhythmias, and deplete SR Ca²⁺ stores contributing to decreased contractility. We and others have identified a class of small molecules derived from 1,4‐benzothiazepines, that enhance the binding affinity of calstabin 2 for RyR2 and reduce the diastolic SR Ca²⁺ leak, even when the channel is PKA hyperphosphorylated. Therefore, this class of compounds has tremendous potential as novel therapeutics for heart failure and cardiac arrhythmias.