C-Kit is a receptor tyrosine kinase used as a surface marker to identify stem cells in several tissues and organs. C-Kit+ cell populations have been found in adult heart, studied as potential cardiac progenitor cells and subsequently explored as a potential target for regenerative treatment after heart injury. C-Kit+ cardiomyocytes have been identified in the injured heart and shown to be involved in the heart regeneration process. C-Kit expression in cardiac cells has been reported extensively in previous studies. However, the role of c-Kit expression and signaling in cardiac cells and cardiac regeneration remains unclear. The goal of this study is to explore role of c-Kit signaling in cardiac cells. C-Kit and its downstream signaling pathways play an important role in survival, proliferation, differentiation and chemotaxis of the adult stem cells such as hematopoietic and germ stem cells, as well endothelial cells and neurons. In this study, it is hypothesized that c-Kit signaling plays a protective role in stressed cardiac cells and is required for cellular protective response to stress. The association of c-Kit expression and signaling with cellular stress was investigated in c-Kit+ cardiac progenitor cells isolated from mouse and human heart tissues, and mouse adult cardiomyocytes. The results showed c-Kit upregulation in response to stress in cardiac progenitor cells and cardiomyocytes performing q-PCR and immunoblot analyses. In addition, mouse and human cardiac progenitor cells with activated c-Kit signaling showed increased growth, proliferation and decreased cell death in response to stress. Overall, these observations indicate the protective role of c-Kit/SCF signaling in cardiac cells and suggest the c-Kit signaling pathway as a possible cardioprotective target in injured heart therapies.