Calcium dependent signaling is highly regulated in cardiomyocytes and determines the force of cardiac muscle contraction. The cardiac ryanodine receptors (RyR2) play important roles in health and disease. Modulation of RyR2 by phosphorylation is required for sympathetic regulation of cardiac function. Abnormal regulation of RyR2 contributes to heart failure, and atrial and ventricular arrhythmias. RyR2 channels are oxidized, nitrosylated, and hyperphosphorylated by protein kinase A (PKA) in heart failure, resulting in “leaky” channels. These leaky RyR2 channels contribute to depletion of calcium from the sarcoplasmic reticulum, resulting in defective cardiac excitation–contraction coupling. In this review, we discuss both the importance of PKA and calcium/calmodulin-dependent kinase II (CaMKII) regulation of RyR2 in health, and how altered phosphorylation, nitrosylation and oxidation of RyR2 channels lead to cardiac disease. Correcting these defects using either genetic manipulation (knock-in) in mice, or specific and novel small molecules ameliorates the RyR2 dysfunction, reducing the progression to heart failure and the incidence of arrhythmias. This article is part of a Special Issue entitled “Calcium Signaling in Heart”.