Apoptosis plays a central role in organs development and homeostasis. Impaired regulation of this process is often associated with the onset of several human diseases, such as developmental disorders and cancer. The last scientific investigations have discovered interesting connections between apoptosis, stem cells, tissue regeneration and cancer. The role of "programmed cell death" in stem cells and tissue engineering is extremely promising; in fact, it holds great potential for regenerative purposes. However, several questions still remain unsolved: do we really know all the main molecular actors able to switch ON/OFF the apoptosis? Is it possible to modulate these players, to obtain a predictable regeneration of tissues and organs? But primarily: should we reconsider the apoptosis as a strategic player in tissue regeneration? In this topical review, we have carefully examined the most recent discoveries about the role of apoptosis in stem cells and, specifically, in mesenchymal stem cells. The pivotal molecules involved in the activation and inhibition of the apoptotic pathways will be carefully described, with the aim to shed an overall light on the complex scenario of stem cell life and death, and on a novel strategy for tissue regeneration.