The Notch pathway has crucial roles in the embryonic life of metazoans, and is essential during development of the cardiovascular system in mammals. It is also involved in regeneration of adult self-renewing tissues. We demonstrated that the Notch pathway is activated in the stressed adult heart. Notch1-receptor signaling takes place in cardiomyocytes and in cardiac precursors, and is activated secondary to stimulated expression of the Notch receptor ligand Jagged1 on the surface of cardiomyocytes. In cardiomyocytes, Notch controls maturation, limits the extent of the hypertrophic response and contribute to cell survival. In cardiac precursors, Notch prevents cardiogenic differentiation, favors proliferation, and facilitates the expansion of a transient amplifying cell compartment. These results suggest that controlled activation of the Notch pathway during the adaptation of the heart to stress should produce beneficial effects via induction of cardiac precursor cell expansion, improvement of cardiomyocyte survival, and reduction of cardiac fibrosis. Therefore, we are currently testing this hypothesis using different approaches in vitro and in vivo. Notch appears to regulate key cellular mechanisms in the mesenchymal stromal cell population, and thereby controls the balance between fibrotic and regenerative repair in the adult heart. Altogether, our findings indicate that Notch represents a promising therapeutic target for inducing regeneration in the adult heart via mobilization of cardiac precursor cells.