MLL5 is an MLL family protein and a candidate tumor suppressor located within the human chromosome band 7q22 that is frequently deleted in myeloid malignancies. In this issue of Blood, 3 independent studies report the first genetic analysis of MLL5 deficiency in mice. All 3 strains of MLL5 knockout mice exhibited defects in hematopoiesis, highlighting the critical role of MLL5 in hematopoietic stem cell functions.