Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes with potent immunosuppressive activity. They are implicated in the regulation of immune responses in many pathological conditions and are closely associated with poor clinical outcomes in cancer. Recent studies have indicated key distinctions between MDSCs and classical neutrophils and monocytes, and, in this Review, we discuss new data on the major genomic and metabolic characteristics of MDSCs. We explain how these characteristics shape MDSC function and could facilitate therapeutic targeting of these cells, particularly in cancer and in autoimmune diseases. Additionally, we briefly discuss emerging data on MDSC involvement in pregnancy, neonatal biology and COVID-19.