Redox signaling, involving electron transfer between nucleophilic and electrophilic molecules, is essential for regulating inflammatory macrophages. Reactive oxygen and nitrogen species (ROS and RNS), along with redox-sensitive metabolites like fumarate and itaconate, modify cysteine residues in target proteins, influencing macrophage function. Recent studies highlight how ROS, RNS, and metabolites regulate macrophage function and contribute to disease. Key tools for assessing redox signaling and unresolved questions are discussed. Macrophages, innate immune cells, perform diverse functions including phagocytosis, cytokine production, and tissue repair. They also play roles in tissue homeostasis and contribute to disease pathology, particularly in metabolic dysfunction and chronic inflammation. Macrophages sense pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) through pattern-recognition receptors (PRRs), altering their phenotype to respond appropriately. ROS, produced by NADPH oxidases (NOX) and mitochondrial electron transport chain (ETC), act as antimicrobial agents and signaling molecules. ROS can regulate cytokine secretion, inflammasome activation, and adaptive immune responses. RNS, derived from nitric oxide (NO), also play roles in microbial killing and inflammatory macrophage function. Redox signaling regulates macrophage signal transduction, gene expression, metabolism, differentiation, and polarization. Post-translational modifications (PTMs) of cysteine residues, such as sulfenylation, S-nitrosylation, glutathionylation, and palmitoylation, are crucial for redox signaling. These modifications regulate protein function, affecting processes like NF-κB signaling, PRRs, and the NLRP3 inflammasome. Metabolites like itaconate and fumarate also modulate redox signaling by inhibiting ROS production and modifying cysteine residues in target proteins. ROS and RNS are critical for macrophage function, including antimicrobial activity, inflammation, and tissue repair. Dysregulation of redox signaling in macrophages contributes to diseases such as chronic granulomatous disease (CGD), neurodegeneration, and sepsis. The antioxidant response, including SODs and NRF2, helps regulate redox homeostasis and prevent excessive inflammation. In summary, redox signaling is essential for macrophage function and disease pathology. Understanding the mechanisms of redox regulation in macrophages is crucial for developing therapeutic strategies to modulate inflammation and disease.Redox signaling, involving electron transfer between nucleophilic and electrophilic molecules, is essential for regulating inflammatory macrophages. Reactive oxygen and nitrogen species (ROS and RNS), along with redox-sensitive metabolites like fumarate and itaconate, modify cysteine residues in target proteins, influencing macrophage function. Recent studies highlight how ROS, RNS, and metabolites regulate macrophage function and contribute to disease. Key tools for assessing redox signaling and unresolved questions are discussed. Macrophages, innate immune cells, perform diverse functions including phagocytosis, cytokine production, and tissue repair. They also play roles in tissue homeostasis and contribute to disease pathology, particularly in metabolic dysfunction and chronic inflammation. Macrophages sense pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) through pattern-recognition receptors (PRRs), altering their phenotype to respond appropriately. ROS, produced by NADPH oxidases (NOX) and mitochondrial electron transport chain (ETC), act as antimicrobial agents and signaling molecules. ROS can regulate cytokine secretion, inflammasome activation, and adaptive immune responses. RNS, derived from nitric oxide (NO), also play roles in microbial killing and inflammatory macrophage function. Redox signaling regulates macrophage signal transduction, gene expression, metabolism, differentiation, and polarization. Post-translational modifications (PTMs) of cysteine residues, such as sulfenylation, S-nitrosylation, glutathionylation, and palmitoylation, are crucial for redox signaling. These modifications regulate protein function, affecting processes like NF-κB signaling, PRRs, and the NLRP3 inflammasome. Metabolites like itaconate and fumarate also modulate redox signaling by inhibiting ROS production and modifying cysteine residues in target proteins. ROS and RNS are critical for macrophage function, including antimicrobial activity, inflammation, and tissue repair. Dysregulation of redox signaling in macrophages contributes to diseases such as chronic granulomatous disease (CGD), neurodegeneration, and sepsis. The antioxidant response, including SODs and NRF2, helps regulate redox homeostasis and prevent excessive inflammation. In summary, redox signaling is essential for macrophage function and disease pathology. Understanding the mechanisms of redox regulation in macrophages is crucial for developing therapeutic strategies to modulate inflammation and disease.