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Calcium (Ca 2+) is a universal second messenger involved in the regulation of various cellular processes, including electrical signaling, contraction, secretion, memory, gene transcription, and cell death. In heart, Ca 2+ governs cardiomyocyte contraction, is central in electrophysiological properties, and controls major signaling pathway implicated in gene transcription. How cardiomyocytes decode Ca 2+ signal to regulate gene expression without interfering with, or being controlled by,“contractile” Ca 2+ that floods the entire cytosol during each heartbeat is still elusive. In this review, we summarize recent findings on nuclear Ca 2+ regulation and its downstream signaling in cardiomyocytes. We will address difficulties in reliable quantification of nuclear Ca 2+ fluxes and discuss its role in the development and progression of cardiac hypertrophy and heart failure. We also point out key open questions to stimulate future …