PTEN deletion in the mouse and in the zebrafish highlights the essential role of this tumor suppressor in the development of myeloid malignancies, in particular acute myeloid leukemia and myeloproliferative disorders. In humans, extensive genetic sequences of myeloid malignancies did not reveal recurrent PTEN mutations and deletions. However, PTEN was shown to be functionally inactivated in several acute myeloid leukemia and chronic myeloid leukemia samples, through both post-trasductional modifications, changes in protein levels and cellular compartmentalization. Notably, non genomic inactivation of PTEN in myeloid malignancies could represent a challenging therapeutic opportunity for these diseases. Targeting those mechanisms that affect PTEN function could indeed promote PTEN reactivation with consequent cancer selective apoptosis induction. In this review we will describe the role of PTEN in the development of myeloid malignancies.