Myeloid derived suppressor cells (MDSCs) are immature myeloid cells characterized by diverse phenotypes and functions. They impair effector functions of immune cells and promote tumor growth, angiogenesis, and tissue damage. In pathologies characterized by chronic inflammation, MDSCs are arrested in their immature state and migrate from the bone marrow to the periphery and to the site of inflammation, where they mediate immunosuppression. When reaching new environments, which exhibit a different array of cytokines, chemokines, and pro-inflammatory mediators, MDSCs sense and adapt to the altered micro-environment by virtue of acquiring different suppressive features/functions that involve changing their cell fate, surface receptors, metabolism and intracellular as well as secreted molecules. This review summarizes some of the latest publications highlighting various layers of MDSC plasticity in relation to different pathologies. We discuss treatments capitalizing on MDSC plasticity aimed at combating MDSCs or manipulating their suppressive activity for improved therapy.