Immune cells and their secreted growth factors play major roles in tumor growth and metastasis. Interplay between the growing tumor and infiltrating immune cells determines the nature of immune response and ultimately, tumor fate. Increased infiltration of protumorigenic immune cells promotes tumor growth as well as dissemination to distant sites. These cells induce immunosuppression that inhibits proliferation and functions of cells of antitumor immune response. One population of immunosuppressive cells that is increasingly gaining attention is myeloid-derived suppressor cells (MDSC). MDSCs are immature myeloid progenitors that suppress T-cell effector functions and promote angiogenesis. MDSC numbers are elevated at both the primary tumor and metastatic sites, including bone. In addition to immunosuppressive functions of MDSCs,we and others have recently discovered a novel function forMDSCs as osteoclast progenitors. Osteolysis is a common complication in the carcinomas of breast, lung, prostate, and multiple myeloma with poor prognosis. Therefore, targeting the functions of MDSCs may exert dual therapeutic effects on immunosuppression and bone pathology. © 2013 American Association for Cancer Research.