Myeloid-derived suppressor cells (MDSCs) represent a heterogenous collection of immature myeloid cells endowed with suppressive function on the immune response. Their presence has been extensively investigated in preclinical models, especially in the context of cancer. One of the major obstacles in their accurate identification has been the definition of an unambiguous phenotype, shared between mice and humans, and clearly correlating with their suppressive function. In this paper, we review the literature concerning the phenotype in mouse and in humans, showing that at least 2 subsets of MDSCs are present under different situations. We also address the role of MDSCs in tumor progression, evaluate the prognostic significance of MDSC in cancer patients, and their possible role as marker of clinical outcome and response to therapy. Finally, we examine the strategies designed to modulate MDSCs in cancer patients, which might represent an innovative approach to enhance the effectiveness of immune-based therapies.