Rationale : The adult heart possesses a pool of progenitor cells stored in myocardial niches, but the mechanisms involved in the activation of this cell compartment are currently unknown. Objective : Ca ²⁺ promotes cell growth raising the possibility that changes in intracellular Ca ²⁺ initiate division of c-kit–positive human cardiac progenitor cells (hCPCs) and determine their fate. Methods and Results : Ca ²⁺ oscillations were identified in hCPCs and these events occurred independently from coupling with cardiomyocytes or the presence of extracellular Ca ²⁺ . These findings were confirmed in the heart of transgenic mice in which enhanced green fluorescent protein was under the control of the c-kit promoter. Ca ²⁺ oscillations in hCPCs were regulated by the release of Ca ²⁺ from the endoplasmic reticulum through activation of inositol 1,4,5-triphosphate receptors (IP3Rs) and the reuptake of Ca ²⁺ by the sarco-/endoplasmic reticulum Ca ²⁺ pump (SERCA). IP3Rs and SERCA were highly expressed in hCPCs, whereas ryanodine receptors were not detected. Although Na ⁺ -Ca ²⁺ exchanger, store-operated Ca ²⁺ channels and plasma membrane Ca ²⁺ pump were present and functional in hCPCs, they had no direct effects on Ca ²⁺ oscillations. Conversely, Ca ²⁺ oscillations and their frequency markedly increased with ATP and histamine which activated purinoceptors and histamine-1 receptors highly expressed in hCPCs. Importantly, Ca ²⁺ oscillations in hCPCs were coupled with the entry of cells into the cell cycle and 5-bromodeoxyuridine incorporation. Induction of Ca ²⁺ oscillations in hCPCs before their intramyocardial delivery to infarcted hearts was associated with enhanced engraftment and expansion of these cells promoting the generation of a large myocyte progeny. Conclusion : IP3R-mediated Ca ²⁺ mobilization control hCPC growth and their regenerative potential.