Macrophages are a diverse set of cells found in all body compartments, with their diversity influenced by ontogenetic origin, organ context, and activation signals from microbial invasion, tissue damage, and adaptive T cell responses. Classic adaptive responses include tolerance, priming, and a range of activation states such as M1, M2, and M2-like. Single-cell analysis has revealed new dimensions to macrophage differentiation and activation, highlighting the role of epigenetic landscapes, transcription factors, and microRNA networks. Macrophage plasticity is crucial in chronic inflammation and is particularly significant in cancer, where it plays a dual role in both pro-tumor and anti-tumor activities. The origin of tissue macrophages is complex, involving both embryonic and adult bone marrow-derived cells, and their function varies across different tissues. Macrophages can exhibit tolerance, where they become unresponsive to microbial agents, and can also be primed for enhanced responsiveness. The plasticity of macrophages is regulated by epigenetic changes, including histone modifications, DNA methylation, and microRNA expression, which influence gene expression and cellular functions. In cancer, macrophages can contribute to tumor initiation, progression, and metastasis, and their function is shaped by the tumor microenvironment (TME). Macrophages in the TME are influenced by various factors such as type 2 cytokines, immunosuppressive cytokines, chemokines, and metabolic products, which drive their polarization and function. Understanding the molecular and cellular mechanisms underlying macrophage plasticity is essential for developing strategies to modulate macrophage function in therapeutic contexts, particularly in cancer treatment.Macrophages are a diverse set of cells found in all body compartments, with their diversity influenced by ontogenetic origin, organ context, and activation signals from microbial invasion, tissue damage, and adaptive T cell responses. Classic adaptive responses include tolerance, priming, and a range of activation states such as M1, M2, and M2-like. Single-cell analysis has revealed new dimensions to macrophage differentiation and activation, highlighting the role of epigenetic landscapes, transcription factors, and microRNA networks. Macrophage plasticity is crucial in chronic inflammation and is particularly significant in cancer, where it plays a dual role in both pro-tumor and anti-tumor activities. The origin of tissue macrophages is complex, involving both embryonic and adult bone marrow-derived cells, and their function varies across different tissues. Macrophages can exhibit tolerance, where they become unresponsive to microbial agents, and can also be primed for enhanced responsiveness. The plasticity of macrophages is regulated by epigenetic changes, including histone modifications, DNA methylation, and microRNA expression, which influence gene expression and cellular functions. In cancer, macrophages can contribute to tumor initiation, progression, and metastasis, and their function is shaped by the tumor microenvironment (TME). Macrophages in the TME are influenced by various factors such as type 2 cytokines, immunosuppressive cytokines, chemokines, and metabolic products, which drive their polarization and function. Understanding the molecular and cellular mechanisms underlying macrophage plasticity is essential for developing strategies to modulate macrophage function in therapeutic contexts, particularly in cancer treatment.