Reactive oxygen species (ROS) molecules are implicated in signal transduction pathways and thereby control a range of biological activities. Immune cells are constantly confronted with ROS molecules under both physiologic and pathogenic conditions. Myeloid-derived suppressor cells (MDSCs) are immunosuppressive, immature myeloid cells and serve as major regulators of pathogenic and inflammatory immune responses. In addition to their own release of ROS, MDSCs often arise in oxidative-stress prone environments such as in tumors or during inflammation and infection. This evidently close relationship between MDSCs and ROS prompted us to summarize what is currently known about ROS signaling within MDSCs and to elucidate how MDSCs use ROS to modulate other immune cells. ROS not only activate anti-oxidative pathways but also induce transcriptional programs that regulate the fate and function of MDSCs. Furthermore, MDSCs release ROS molecules as part of a major mechanism to suppress T cell responses. Targeting redox-regulation of MDSCs thus presents a promising approach to cancer therapy and the role of redox-signaling in MDSCs in other disease states such as infection, inflammation and autoimmunity would appear to be well worth investigating.