IFNα therapy has been shown to deplete the MPN HSPC pool through activation and exit from a quiescent state and induction of differentiation. These biological effects seem to be influenced by driver mutation status, JAK2V617F homozygosity, and dosing approach. The clinical implication of the findings from Mosca et al is shown here in the context of other recognized predictors of IFNα outcome. The goal of therapeutic intervention in ET/PV is primarily thrombotic risk reduction, which is believed to be achieved through attainment of a CHR and secondarily disease course modification through a CMR. CHR, complete hematologic remission; CMR, complete molecular remission; VAF, variant allele frequency.