This Review provides an update on ryanodine receptors (RyRs) and their role in human diseases of heart, muscle, and brain. Calcium (Ca²⁺) is a requisite second messenger in all living organisms. FromC. elegans to mammals, Ca²⁺ is necessary for locomotion, bodily functions, and neural activity. However, too much of a good thing can be bad. Intracellular Ca²⁺ overload can result in loss of function and death. Intracellular Ca²⁺ release channels evolved to safely provide large, rapid Ca²⁺ signals without exposure to toxic extracellular Ca²⁺. RyRs are intracellular Ca²⁺ release channels present throughout the zoosphere. Over the past 35 years, our knowledge of RyRs has advanced to the level of atomic-resolution structures revealing their role in the mechanisms underlying the pathogenesis of human disorders of heart, muscle, and brain. Stress-induced RyR mediated intracellular Ca²⁺ leak in the heart can promote heart failure and cardiac arrhythmias. In skeletal muscle, RyR1 leak contributes to muscle weakness in inherited myopathies, to age-related loss of muscle function and cancer-associated muscle weakness, and to impaired muscle function in muscular dystrophies, including Duchenne. In the brain, leaky RyR channels contribute to cognitive dysfunction in Alzheimer’s disease, posttraumatic stress disorder, and Huntington’s disease. Novel therapeutics targeting dysfunctional RyRs are showing promise.