New therapies targeting critical elements of the cell cycle open novel and attractive avenues for the treatment of cancer patients. At present, the number of clinical trials that are registered with the European Organization for Research and Treatment of Cancer (EORTC) and with the US National Cancer Institute, which investigate the efficacy of Polo-like kinase 1 (Plk1) inhibitors against solid tumors and different types of leukemia is growing. Plks are important regulators of mitotic progression. Plk1, the best characterized mammalian Plk, has become an attractive target for cancer drug development, because most types of cancer appear to be addicted to the non-oncogene Plk1. Here, the authors discuss the role of Plk1 and the potential tumor suppressor gene Plk2 in acute myeloid leukemia (AML).