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MZF1 is a transcription factor belonging to the Krüppelfamily of zinc finger proteins, expressed in totipotent hemopoietic cells as well as in myeloid progenitors. Here we have inactivatedMzfi1 by gene targeting. Mzf1 ^−/− mice develop lethal neoplasias characterized by the infiltration and complete disruption of the liver architecture by a monomorphic population of cells of myeloid origin reminiscent of human chloromas.Mzf1 inactivation results in a striking increase of the autonomous cell proliferation and of the ability ofMzf1 ^−/− hemopoietic progenitors to sustain long-term hemopoiesis. These findings demonstrate that Mzf1 can act as a tumor/growth suppressor in the hemopoietic compartment.