Cell cycle progression in dividing cells, characterized by faithful replication of the genomic materials and duplication of the original cell, is fundamental for growth and reproduction of all mammalian organisms. Functional maturation of postmitotic cells, however, requires cell cycle exit and terminal differentiation. In mature postmitotic cells, many cell cycle proteins remain to be expressed, or can be induced and reactivated in pathological conditions such as traumatic injury and degenerative diseases. Interestingly, elevated levels of cell cycle proteins in postmitotic cells often do not induce proliferation, but result in aberrant cell cycle reentry and cell death. At present, the cell cycle machinery is known predominantly for regulating cell cycle progression and cell proliferation, albeit accumulating evidence indicates that cell cycle proteins may also control cell death, especially in postmitotic tissues. Herein, we provide a brief summary of these findings and hope to highlight the connection between cell cycle reentry and postmitotic cell death. In addition, we also outline the signaling pathways that have been identified in cell cycle-related cell death. Advanced understanding of the molecular mechanisms underlying cell cycle-related death is of paramount importance because this knowledge can be applied to develop protective strategies against pathologies in postmitotic tissues. Moreover, a full-scope understanding of the cell cycle machinery will allow fine tuning to favor cell proliferation over cell death, thereby potentially promoting tissue regeneration.