Cancer immunotherapy has focused on inducing and expanding CTLs and improving the immune recognition of weak antigenic determinants expressed by tumors. However, few positive clinical outcomes have been reported due, in part, to tumor-associated immunologic tolerance, supporting the need for an emphasis on overcoming immunosuppression. Systemic immunosuppression is associated with abnormal myelopoiesis secondary to tumor growth, myelosuppressive therapy, and growth factor administration and subsequent expansion/mobilization of bone marrowd erived immunosuppressive cells. These myeloid-derived suppressor cells (MDSC) reduce activated T-cell number and inhibit their function by multiple mechanisms, including depletion of L-arginine by arginase-1 (ARG1) production of nitric oxide, reactive oxygen species, and reactive nitrogen oxide species by inducible nitric oxide synthase. Increased numbers of MDSCs are associated with neoplastic, inflammatory, infectious, and graft-versus-host diseases where they restrain exuberant or novel T-cell responses. In this review, we discuss critical components of MDSC-mediated suppression of T-cell function, including cellular expansion and activationinduced secretion of immunosuppressive mediators. Both components of MDSC bioactivity are amenable to pharmacologic intervention as discussed herein. We also focus on the relationship between MDSCs, tumor growth, therapeutic responses, and the mechanisms of cellular expansion, activation, and immunosuppression.Host immunity has a critical role in regulating tumor outgrowth and patient survival; however, the expansion of tumor-specific T cells is also limited by tumor growth. Recently, there has been a resurgence of interest in myeloid-derived cells in association with their role in tumor progression and potential to limit therapeutic responses. Myeloid-derived suppressor cells (MDSC) are increased in numerous pathologic conditions, including infections, inflammatory diseases, graft-versus-host disease, traumatic stress, and neoplastic diseases (1, 2), and serve to limit T-cell responses. Tumor growth results in the expansion of this highly heterogeneous cellular population, which includes granulocytic, macrophage, dendritic cell, and early myeloid progenitors. MDSCs inhibit not only activation of T cells by anti-CD3 and superantigen, but also antigen-specific CD4 + and CD8 + T-cell responses. The mechanisms of MDSC immunosuppression are diverse, including up-regulation of reactive oxygen species (ROS), nitric oxide (NO), and L-arginine metabolism, as well as immunosuppressive cytokines. MDSCs were initially described in the late 1970s when they were identified as natural suppressor cells and defined as cells without lymphocyte-lineage markers that could suppress lymphocyte response to immunogens and mitogens (3 -5). MDSCs in mice are CD11b and Gr1 positive (6, 7) and also express CD31 (8), CD124, interleukin (IL)-4 receptor a-chain (9) and CD115, and macrophage-colony stimulating factor receptor (10). Human MDSC equivalents we...