The death of all the cancer cells in a tumor is the ultimate goal of cancer therapy. Therefore, much of the current effort in cancer research is focused on activating cellular machinery that facilitates cell death such as factors involved in causing apoptosis. However, recently, a number of studies point to some counterintuitive roles for apoptotic caspases in radiation therapy as well as in tissue regeneration. It appears that a major function of apoptotic caspases is to facilitate tissue regeneration and tumor cell repopulation during cancer therapy. Because tumor cell repopulation has been shown to be important for local tumor relapse, understanding the molecular mechanisms behind tumor repopulation would be important to enhance cancer radiotherapy. In this review, we discuss our current knowledge of these potentially paradigm-changing phenomena and mechanisms in various organisms and their implications on the development of novel cancer therapeutics and strategies.