In two recent publications, Pier Paolo Pandolfi and colleagues report that the microRNA miR-22 has oncogenic activities in hematological malignancies (Cell Stem Cell 13, 87–101, 2013) and in breast cancer (Cell 154, 311–324, 2013). The authors showed that miR-22 expression is often higher in myelodysplastic syndrome (MDS) and is correlated with poor survival rate. They generated transgenic mice expressing miR-22 in the hematopoietic compartment; these mice developed MDS and hematological malignancies. The authors identified TET2, which encodes an enzyme that catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), as a direct target of miR-22 and showed that miR-22 overexpression reduced global 5hmC levels. Separately, the authors showed that high expression of miR-22 associates with advanced breast tumor stage and poor survival rate. The authors generated transgenic mice expressing miR-22 in mammary glands; these mice developed mammary hyperplasia and mammary tumor formation with lung metastases. The authors showed that miR-22 directly targets TET enzymes for repression, resulting in reduced global 5hmC levels. Specifically, miR-22 overexpression and TET repression caused reduction of promoter 5hmC and reduced expression of miR-200, a microRNA with known tumor suppressor functions. Together, these papers identify oncogenic functions for miR-22 and a tumorigenic pathway involving the deregulation of TET enzymes.