In noncontractile cells, a sustained increase in total cytoplasmic Ca 2+ concentration is typically needed to activate the intracellular protein phosphatase calcineurin, leading to dephosphorylation of the transcription factor nuclear factor of activated T cells (NFAT), its nuclear translocation, and induction of gene expression. It remains a mystery exactly how Ca 2+ -dependent signaling pathways, such as that mediated by calcineurin-NFAT, are regulated in contracting cardiac myocytes given the highly specialized manner in which Ca 2+ concentration rhythmically cycles in excitation-contraction coupling. Here, we critically review evidence that supports the hypothesis that calcineurin-NFAT signaling is regulated by contractile Ca 2+ transients in cardiac myocytes.The primary function of the heart is to contract and pump blood in proportion to tissue needs. Each individual cardiac contraction (systole) depends on a transient increase in the cytosolic free Ca 2+ concentration (the systolic Ca 2+ transient, also commonly termed "contractile Ca 2+ ") to activate the contractile proteins that elicit pressure development and ejection of blood. Cardiac relaxation (diastole), in turn, depends on a decrease in the cytosolic free Ca 2+ concentration. The frequency and amplitude of the systolic Ca 2+ transient are regulated by neuroendocrine inputs and effectors to dynamically alter myocyte contractility and cardiac output (1). Alterations in contractility associated with such changes in the Ca 2+ transient can be achieved by physiological stimuli, such as in response to exercise, or by pathologic stimuli, in response to hypertension or after myocardial infarction injury.In general, pathologic disease states increase ventricular wall stress, necessitating an increase in contractile Ca 2+ to maintain cardiac output. Persistent pathological stress on the heart also leads to cardiac hypertrophy, circumstantially linking increases in contractile Ca 2+ with pathological cardiomyocyte growth. Various physiologic stimuli, such as adolescent development, pregnancy, and aerobic exercise training, also enhance cardiac output and contractile Ca 2+ in association with hypertrophic growth. Therefore, both physiological (exercise) and pathological (hypertension) stimulation elicit increases in contractile Ca 2+ , and both conditions lead to cardiac hypertrophy. However, physiological and pathological hypertrophy are likely transduced by fundamentally different signaling pathways, despite the commonality of enhanced contractile Ca 2+ (2).Regulation of contractile Ca 2+ in cardiac myocytes involves a highly specialized system of ion channels, pumps, exchangers, and microdomains (1). Contraction starts when depolarization *Corresponding authors.