AbstractMitosis is the process whereby an eukaryotic cell divides into two identical copies. Different multiprotein complexes are involved in the fine regulation of cell division, including the mitotic promoting factor and the anaphase promoting complex. Prolonged mitosis can result in cellular division, cell death, or mitotic slippage, the latter leading to a new interphase without cellular division. Mitotic slippage is one of the causes of genomic instability and has an important therapeutic and clinical impact. It has been widely studied in solid tumors but not in hematological malignancies, in particular, in acute leukemia. We review the literature data available on mitotic regulation, alterations in mitotic proteins occurring in acute leukemia, induction of prolonged mitosis and its consequences, focusing in particular on the balance between cell death and mitotic slippage and on its therapeutic potentials. We also present the most recent preclinical and clinical data on the efficacy of second-generation mitotic drugs (CDK1-Cyclin B1, APC/CCDC20, PLK, Aurora kinase inhibitors). Despite the poor clinical activity showed by these drugs as single agents, they offer a potential therapeutic window for synthetic lethal combinations aimed to selectively target leukemic cells at the right time, thus decreasing the risk of mitotic slippage events.