Polycythemia vera (PV) and essential thrombocythemia (ET) may rarely evolve into acute leukemia as part of their natural history. Cytogenetic abnormalities and the use of alkylating agents can enhance the risk of this transformation. Hydroxyurea (HU) has a limited, if any, leukemogenic potential and should be considered the current cytotoxic drug for patients at high risk for thrombotic complications, ie, those with age above 60 years or previous thrombotic events. Interferon-alpha (IFN-alpha) and anagrelide are known not to be leukemogenic and might have a role in younger patients. However, no controlled clinical trials of efficacy and safety are available for these two drugs and the occurrence of side effects may be a limiting factor for their widespread use.