Macrophages are essential for immunity, development, and tissue homeostasis. They are part of the innate immune system and can be activated by various stimuli, including cytokines from helper T cells. Macrophages release cytokines that mediate communication between immune and non-immune cells, playing a key role in the transition from innate to adaptive immunity. Cytokines can be proinflammatory or anti-inflammatory, and their dysregulation is implicated in various diseases, including chronic inflammation and allergy. Macrophages release cytokines through a series of spatiotemporally regulated pathways, involving multi-protein complexes that guide cytokines from their point of synthesis to their release into the extracellular environment. These trafficking proteins, many discovered in yeast, coordinate organelle fusion steps necessary for cytokine release. This review discusses the functions of cytokines secreted by macrophages and summarizes their release mechanisms. It highlights how pathogens subvert cytokine release for their survival. Proinflammatory cytokines such as TNF, IL-1, IL-6, IL-12, and IL-18 are involved in immune responses, while anti-inflammatory cytokines like IL-10 and TGF-β regulate inflammation and immune responses. Chemokines, such as CXCL1, CXCL2, CCL5, CXCL8, CXCL9, CXCL10, and CXCL11, guide immune cell migration and are involved in inflammation and tissue repair. Macrophages can be classified into classically activated (M1) and alternatively activated (M2) types, which secrete different cytokines and have distinct functions. M1 macrophages are proinflammatory and microbicidal, while M2 macrophages are immunosuppressive and involved in tissue repair. Pathogens, such as Mycobacterium ulcerans and Leishmania, have evolved mechanisms to disrupt cytokine secretion, aiding their survival and dissemination. Mycobacterium ulcerans uses mycolactone to inhibit cytokine production, while Leishmania promastigotes use GP63 to enhance TNF and IL-6 release, promoting inflammation and infection. Understanding these mechanisms is crucial for developing strategies to modulate macrophage function in disease.Macrophages are essential for immunity, development, and tissue homeostasis. They are part of the innate immune system and can be activated by various stimuli, including cytokines from helper T cells. Macrophages release cytokines that mediate communication between immune and non-immune cells, playing a key role in the transition from innate to adaptive immunity. Cytokines can be proinflammatory or anti-inflammatory, and their dysregulation is implicated in various diseases, including chronic inflammation and allergy. Macrophages release cytokines through a series of spatiotemporally regulated pathways, involving multi-protein complexes that guide cytokines from their point of synthesis to their release into the extracellular environment. These trafficking proteins, many discovered in yeast, coordinate organelle fusion steps necessary for cytokine release. This review discusses the functions of cytokines secreted by macrophages and summarizes their release mechanisms. It highlights how pathogens subvert cytokine release for their survival. Proinflammatory cytokines such as TNF, IL-1, IL-6, IL-12, and IL-18 are involved in immune responses, while anti-inflammatory cytokines like IL-10 and TGF-β regulate inflammation and immune responses. Chemokines, such as CXCL1, CXCL2, CCL5, CXCL8, CXCL9, CXCL10, and CXCL11, guide immune cell migration and are involved in inflammation and tissue repair. Macrophages can be classified into classically activated (M1) and alternatively activated (M2) types, which secrete different cytokines and have distinct functions. M1 macrophages are proinflammatory and microbicidal, while M2 macrophages are immunosuppressive and involved in tissue repair. Pathogens, such as Mycobacterium ulcerans and Leishmania, have evolved mechanisms to disrupt cytokine secretion, aiding their survival and dissemination. Mycobacterium ulcerans uses mycolactone to inhibit cytokine production, while Leishmania promastigotes use GP63 to enhance TNF and IL-6 release, promoting inflammation and infection. Understanding these mechanisms is crucial for developing strategies to modulate macrophage function in disease.