The mechanisms and machinery regulating calcium cycling through the sarcoplasmic reticulum (SR), a secretory pathway calcium storage organelle, remain incompletely understood, and further insight is critical for discerning normal and diseased heart function. An overlooked component is luminal SR protein phosphorylation. Our lab recently identified an atypical protein kinase in the secretory pathway lumen, Fam20C, and have demonstrated its role in calcium homeostasis for proper development of bone and teeth. This novel kinase phosphorylates Ser residues within highly conserved Ser-x-Glu/pSer (SxE) motifs, and is interestingly responsible for the overwhelming majority of secretory pathway protein phosphorylation. Therefore, we hypothesize that Fam20C phosphorylates proteins in the cardiac SR lumen, and that this phosphorylation will play an important role in SR calcium cycling. Indeed, we demonstrate that Fam20C phosphorylates SR proteins that have SxE sites, including Calsequestrin 2, Triadin, Sarcalumenin, Calreticulin, and Calumenin, all of which play important roles in SR calcium handling. Furthermore, we developed a cardiac specific Fam20C knockout mouse model. Following transverse aortic constriction (TAC) induced pressure overload, we find that Fam20C ablation reduces cardiac function and shows significantly increased signs of heart failure. Also, Fam20C ablation following TAC causes reduction in key regulators of SR calcium cycling, including SR Calcium-ATPase type 2a (SERCA2a) and phospholamban. Our results establish Fam20C as a novel cardioprotective signaling molecule, and open new avenues for potential therapeutic approaches to cardiovascular disease.