Tumor cells and microorganisms manipulate the immune system to minimize any counter response in order to survive. Myeloid-derived suppressor cells (MDSC) in the mouse represent activated Gr-1⁺ CD11b⁺ myeloid precursor cells. Activation may occur through endogenous or exogenous factors leading to the suppression of immune responses. Under steady state conditions the same precursors differentiate into dendritic cells, macrophages and neutrophils. Their linkage to tumor progression and several suppression mechanisms employing the arginine metabolism are well documented, but knowledge of their role in chronic infections, autoimmune diseases and graft-versus-host reactions is just emerging. Several factors have been described to promote MDSC expansion and activation in bone marrow, spleen and tumor sites. New evidence suggests that the Gr-1 antibody itself may differentially trigger myelopoiesis under steady state conditions or induce apoptosis in inflammatory situations after binding to a common epitope expressed on Ly-6C and Ly-6G molecules, respectively. Moreover, two subsets of neutrophil- and monocyte-related MDSC have been described in tumor-bearing and healthy mice. In the present review, we summarize some early work leading to recent findings on these two MDSC subsets, the factors supporting MDSC expansion and activation, as well as novel insights on Gr-1 antibody functions.