Genesis of monocytic myeloid-derived suppressor cells (M-MDSC) during infectious diseases. Hypothetical models were derived from ex vivo results, correlative studies in animal models as well as clinical observations. Immature myeloid cells (IMC) are generated either in bone marrow or in spleen as a consequence of emergency myelopoiesis. Growth factors, cytokines, and lipids promote progression of hematopoietic stem cells (HSC) toward common myeloid progenitor (CMP) development and subsequent IMC genesis. Combination of cytokines as well as direct stimulation of selected microbial receptors by various microorganisms may activate or reprogram circulating monocytes toward M-MDSC. M-MDSC are recruited in various organs where they exert suppressive function and modulate manifestations and outcome of the disease. Abbreviations: AdV, adenovirus; AKT, protein kinase B; ERK, extracellular signal-regulated kinase; GM-CSF, granulocyte-macrophage colony stimulating factor; gp120, glycoprotein 120; HBV, hepatitis B virus; HBVsAg, HBV soluble antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IAV, influenza A virus; IFN-γ, interferon gamma; IL-6, interleukin 6; LPS, lipopolysaccharide; LP-BM5, virus murine acquired-immune deficiency syndrome (AIDS); MHV-68, murine herpesvirus 68; MyD88, myeloid differentiation primary response gene 88; NF-κB, nuclear factor “kappa-light-chain-enhancer” of activated B-cells; PI3K, phosphatidylinositide 3-kinase; PGE2, prostaglandin E2; STAT, signal transducer and activator of transcription; SIV, simian immunodeficiency virus; tat, trans-activator of transcription; TLR, toll-like receptor.