Ryanodine receptors (RyR) regulate intracellular Ca²⁺ release in many cell types and have been implicated in a number of inherited human diseases. Over the past 15years genetically engineered mouse models have been developed to elucidate the role that RyRs play in physiology and pathophysiology. To date these models have implicated RyRs in fundamental biological processes including excitation–contraction coupling and long term plasticity as well as diseases including malignant hyperthermia, cardiac arrhythmias, heart failure, and seizures. In this review we summarize the RyR mouse models and how they have enhanced our understanding of the RyR channels and their roles in cellular physiology and disease.