Redox signaling, involving the transfer of electrons from nucleophilic to electrophilic molecules, is crucial for regulating inflammatory macrophages. Reactive oxygen/nitrogen species (ROS and RNS) and redox-sensitive metabolites like fumarate and itaconate play key roles in this process. ROS, primarily superoxide and hydrogen peroxide, are produced by NADPH oxidases and mitochondria, and they oxidize cysteine residues in target proteins, altering their function. RNS, mainly nitric oxide (NO), are derived from arginine and are essential for microbial killing and inflammatory responses. Redox signaling regulates macrophage functions such as phagocytosis, cytokine production, and antigen presentation through post-translational modifications (PTMs) of cysteine residues. These PTMs include oxidation, glutathionylation, S-nitrosylation, and palmitoylation, which can be reversible or irreversible. The review highlights the latest evidence on how ROS, RNS, and metabolites regulate macrophage function, the tools to assess redox signaling, and the impact of dysregulated redox signaling in diseases such as chronic granulomatous disease, inflammatory bowel disease, and rheumatoid arthritis. Key questions remain regarding the specificity and breadth of PTMs and their mechanisms of action.Redox signaling, involving the transfer of electrons from nucleophilic to electrophilic molecules, is crucial for regulating inflammatory macrophages. Reactive oxygen/nitrogen species (ROS and RNS) and redox-sensitive metabolites like fumarate and itaconate play key roles in this process. ROS, primarily superoxide and hydrogen peroxide, are produced by NADPH oxidases and mitochondria, and they oxidize cysteine residues in target proteins, altering their function. RNS, mainly nitric oxide (NO), are derived from arginine and are essential for microbial killing and inflammatory responses. Redox signaling regulates macrophage functions such as phagocytosis, cytokine production, and antigen presentation through post-translational modifications (PTMs) of cysteine residues. These PTMs include oxidation, glutathionylation, S-nitrosylation, and palmitoylation, which can be reversible or irreversible. The review highlights the latest evidence on how ROS, RNS, and metabolites regulate macrophage function, the tools to assess redox signaling, and the impact of dysregulated redox signaling in diseases such as chronic granulomatous disease, inflammatory bowel disease, and rheumatoid arthritis. Key questions remain regarding the specificity and breadth of PTMs and their mechanisms of action.