The immunosuppressive tumor microenvironment represents not only one of the key factors stimulating tumor progression but also a strong obstacle for efficient tumor immunotherapy. Immunosuppression was found to be associated with chronic inflammatory mediators including cytokines, chemokines and growth factors produced by cancer and stroma cells. Long-term intensive production of these factors induces the formation of myeloid-derived suppressor cells (MDSCs) representing one of the most important players mediating immunosuppression. Moreover, MDSCs could not only inhibit anti-tumor immune reactions but also directly stimulate tumor growth and metastasis. Therefore, understanding the mechanisms of their generation, expansion, recruitment and activation is required for the development of novel strategies for tumor immunotherapy.