The role of Ca2 signaling in triggering hypertrophy was investigated in neonatal rat cardiomyocytes in vitro. We show that an increase in cell size and sarcomere reorganization were elicited by receptor agonists such as Angiotensin II, aldosterone, and norepinephrine and by a small rise in medium KCl concentration, a treatment devoid of direct effects on receptor functions. All these treatments increased the frequency of spontaneous [Ca2] transients, caused nuclear translocation of transfected NFAT(GFP), and increased the expression of a NFAT-sensitive reporter gene. There was no increase in Ca2 spark frequency in the whole cell or in the perinuclear region under these conditions. Hypertrophy and NFAT translocation but not the increased frequency of [Ca2] transients were inhibited by the calcineurin inhibitor cyclosporine A. Hypertrophy by the different stimuli was insensitive to inhibition of myofilament contraction. We concluded that calcineurin–NFAT can act as integrators of the contractile Ca2 signal, and that they can decode alterations in the frequency even of rapid Ca2 oscillations.