Myeloid-derived suppressor cells (MDSC) have recently emerged as one of the central regulators of the immune system. In recent years, interest in understanding MDSC biology and applying MDSC for therapeutic purpose has exploded exponentially. Despite recent progress in MDSC biology, the mechanisms underlying MDSC development from expansion and activation to polarization in different diseases remain poorly understood. More recent studies have demonstrated that two MDSC subsets, M (monocytic)-MDSC and G (granulocytic)-MDSC, are able to polarize from a classically activated phenotype (M1) to an alternatively activated one (M2), or vice versa, in tumor-bearing mice. This phenotypic polarization affects MDSC function and disease progression. In this article, we summarize and discuss polarization, mechanism and therapeutic potential of MDSC. An emphasis is placed on the emerging concept of reprogramming MDSC polarization as a therapeutic strategy.