In recent years, several studies have shown that IFN-α2 is able to induce molecular remissions with undetectable JAK2V617F in a subset of patients with essential thrombocythemia (ET) and polycythemia vera (PV), even with normalization of the bone marrow and sustained molecular remissions after discontinuation of IFN-α2. Accordingly, interest in using IFN-α2 in the treatment of patients with PV and related neoplasms has been revived. This article highlights the current status of IFN-α2 in the treatment of patients with ET, PV, primary myelofibrosis and myelofibrosis following ET and PV. In the context of being able to induce ‘minimal residual disease’ in a subset of patients after long-term treatment with IFN-α2, the current risk-stratification systems used for treatment decisions are being challenged. It is argued that in 2011, the bulk of evidence for the efficacy and safety of pegylated interferons in treating patients with these neoplasms favors the upfront use of pegylated interferons, the goal being to influence the development of the disease at the molecular level and revert patients to a stage of ‘minimal residual disease/operational cure‘ instead of progressive clonal evolution, genomic instability and leukemic or myelofibrotic transformation during long-term treatment with hydroxyurea.