The mononuclear phagocyte system (MPS) is a cell population derived from progenitor cells in the bone marrow, and comprising monocytes, macrophages, osteoclasts, dendritic cells, and microglia. Homeostasis of the MPS and response to physiological stress is under the control of signaling molecules and nuclear factors; among them, macrophage-colony-stimulating factor (M-CSF) controls monocyte/macrophage lineage development. Here we discuss the implication of Ifi204, a M-CSF-responsive gene, in the proliferation and differentiation of monocytes/macrophages. Ifi204 is a member of the interferon-inducible p200 family of proteins, and was found to be an important regulator of differentiation of both skeletal and cardiac muscles and osteogenesis. Ifi204 is expressed at the early stages of differentiation of MPS cells and later in the monocyte/macrophage lineage. IFI16, the closest Ifi protein in human, is expressed all along the the monocytic lineage. In MPS cells, Ifi204 expression is induced by interferons but also by various stimuli, independently of the presence of interferon. Enforced expression of p204 in interleukin-3 (IL3)-dependent FD-Fms cell line strongly decreased both IL3- and M-CSF-dependent proliferation and conversely favored macrophage differentiation of FD-Fms cells in response to M-CSF. Altogether, data enlighten a role of Ifi204 as a regulator of monocyte/macrophage differentiation and make possible a connection with other myeloid regulators.