The receptor for macrophage colony-stimulating factor (M-CSF) is expressed in monocytes/macrophages and their progenitor cells and stimulates both the growth and development of the blood-cell lineage. Although the specific components positively regulating M-CSF receptor signaling have been relatively well defined, it is now clear that important mechanisms to control the signaling cascades also exist. This review discusses the most recent results concerning the negative regulatory molecules for M-CSF receptor signaling. In particular, we focus on negative molecules for both proliferation of monocytes/macrophages and differentiation into mature cells.