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, including cancer, chronic infection, sepsis, and autoimmunity. Recent studies have highlighted key differences between MDSCs and classical neutrophils and monocytes, and this review discusses new data on their genomic and metabolic characteristics. These characteristics shape MDSC function and could facilitate therapeutic targeting, particularly in cancer and autoimmune diseases. Emerging data also suggest roles for MDSCs in pregnancy, neonatal biology, and COVID-19. MDSCs are classified into granulocytic/polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs), based on their origin from granulocytic or monocytic myeloid cell lineages. PMN-MDSCs are characterized by their ability to inhibit immune responses, including those mediated by T cells, B cells, and natural killer (NK) cells. They share key biochemical features with classical neutrophils and monocytes, including the upregulation of signal transducer and activator of transcription 3 (STAT3). MDSCs have distinct transcriptional profiles characterized by the expression of pro-inflammatory and immunosuppressive pathways. Their metabolic functions are characterized by increased accumulation of lipids and fatty acid oxidation (FAO), which promotes their suppressive activity, and a switch to glycolysis. MDSCs also exhibit altered lipid metabolism, with increased accumulation of lipids and the upregulation of genes associated with ER stress and the unfolded protein response (UPR). MDSCs play a critical role in cancer by promoting metastasis through the formation of the premetastatic niche. They facilitate the escape of tumour cells by suppressing immune cells, inducing matrix remodelling, and promoting angiogenesis. MDSCs also contribute to the progression of cancer by suppressing T cell function through the release of reactive oxygen species (ROS), arginase 1, and prostaglandin E2 (PGE2). In autoimmune diseases, MDSCs have been implicated in the progression of conditions such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus (SLE). Increased frequencies of MDSCs have been observed in patients with relapsing-remitting multiple sclerosis during relapse, but decreased frequencies in secondary progressive multiple sclerosis. MDSCs have also been found to accumulate in murine models of asthma, experimental autoimmune encephalomyelitis (EAE), SLE, and collagen-induced arthritis, where their presence correlates with T helper 17 (TH17) cell accumulation and increased disease severity. Therapeutic targeting of MDSCs in cancer and autoimmune diseases is an area of active research. Strategies include blocking MDSC recruitment, inhibMyeloid-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, including cancer, chronic infection, sepsis, and autoimmunity. Recent studies have highlighted key differences between MDSCs and classical neutrophils and monocytes, and this review discusses new data on their genomic and metabolic characteristics. These characteristics shape MDSC function and could facilitate therapeutic targeting, particularly in cancer and autoimmune diseases. Emerging data also suggest roles for MDSCs in pregnancy, neonatal biology, and COVID-19. MDSCs are classified into granulocytic/polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs), based on their origin from granulocytic or monocytic myeloid cell lineages. PMN-MDSCs are characterized by their ability to inhibit immune responses, including those mediated by T cells, B cells, and natural killer (NK) cells. They share key biochemical features with classical neutrophils and monocytes, including the upregulation of signal transducer and activator of transcription 3 (STAT3). MDSCs have distinct transcriptional profiles characterized by the expression of pro-inflammatory and immunosuppressive pathways. Their metabolic functions are characterized by increased accumulation of lipids and fatty acid oxidation (FAO), which promotes their suppressive activity, and a switch to glycolysis. MDSCs also exhibit altered lipid metabolism, with increased accumulation of lipids and the upregulation of genes associated with ER stress and the unfolded protein response (UPR). MDSCs play a critical role in cancer by promoting metastasis through the formation of the premetastatic niche. They facilitate the escape of tumour cells by suppressing immune cells, inducing matrix remodelling, and promoting angiogenesis. MDSCs also contribute to the progression of cancer by suppressing T cell function through the release of reactive oxygen species (ROS), arginase 1, and prostaglandin E2 (PGE2). In autoimmune diseases, MDSCs have been implicated in the progression of conditions such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus (SLE). Increased frequencies of MDSCs have been observed in patients with relapsing-remitting multiple sclerosis during relapse, but decreased frequencies in secondary progressive multiple sclerosis. MDSCs have also been found to accumulate in murine models of asthma, experimental autoimmune encephalomyelitis (EAE), SLE, and collagen-induced arthritis, where their presence correlates with T helper 17 (TH17) cell accumulation and increased disease severity. Therapeutic targeting of MDSCs in cancer and autoimmune diseases is an area of active research. Strategies include blocking MDSC recruitment, inhib