Abnormal Ca²⁺ cycling is important in various cardiac diseases. Evidence has accumulated that dysregulation of Ca²⁺ release from the ryanodine receptor (RyR2) plays a significant role in cardiac dysfunction. Spontaneous Ca²⁺ release through RyR2 during diastole decreases sarcoplasmic reticulum (SR) Ca²⁺ content, and also induces delayed after depolarization (DAD) as a substrate for lethal arrhythmia. Several disease-linked mutations in the RyR have been reported in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) or arrythmogenic right ventricular cardiomyopathy type 2 (ARVC2). The unique distribution of these mutation sites has produced the concept that the interaction among the putative regulatory domains within the RyR may play a key role in regulating the channel opening, and that there seems to be a common abnormality in the channel disorder between heart failure and CPVT/ARVC2. We review here the considerable body of evidence regarding defective channel gating of RyR2 in the pathogenesis of heart failure and lethal arrhythmia.