Macrophages are diverse cells present in all body compartments, with their diversity influenced by ontogenetic origin, organ context, and activation signals. They exhibit a wide range of activation states, including M1 and M2, and can retain long-term imprinting from microbial encounters. Single-cell analysis has revealed the complexity of macrophage differentiation and activation, with epigenetic landscapes, transcription factors, and microRNA networks underlying their adaptability. Macrophage plasticity is essential in chronic inflammation and plays a key role in various diseases, including cancer. Macrophages originate from both embryonic and adult monocytes, with evidence suggesting a dual origin in humans. They play critical roles in development, homeostasis, and disease, including chronic inflammation and cancer. Macrophage plasticity involves priming, polarized activation, training, and tolerance, with microRNAs and epigenetic modifications playing key roles in regulating their function and response to environmental cues. In cancer, macrophages can be pro- or anti-tumor, depending on the signals they receive. They contribute to tumor progression, metastasis, and the tumor microenvironment (TME), which is characterized by acidosis and metabolic changes. Macrophages can be influenced by various factors, including cytokines, chemokines, and exosomes, which shape their function and promote immune evasion. The plasticity of macrophages is crucial in cancer, with their ability to adapt to the TME and influence tumor progression. Understanding the molecular mechanisms underlying macrophage plasticity, including epigenetic regulation, microRNA expression, and metabolic changes, is essential for developing therapeutic strategies to combat cancer and other diseases.Macrophages are diverse cells present in all body compartments, with their diversity influenced by ontogenetic origin, organ context, and activation signals. They exhibit a wide range of activation states, including M1 and M2, and can retain long-term imprinting from microbial encounters. Single-cell analysis has revealed the complexity of macrophage differentiation and activation, with epigenetic landscapes, transcription factors, and microRNA networks underlying their adaptability. Macrophage plasticity is essential in chronic inflammation and plays a key role in various diseases, including cancer. Macrophages originate from both embryonic and adult monocytes, with evidence suggesting a dual origin in humans. They play critical roles in development, homeostasis, and disease, including chronic inflammation and cancer. Macrophage plasticity involves priming, polarized activation, training, and tolerance, with microRNAs and epigenetic modifications playing key roles in regulating their function and response to environmental cues. In cancer, macrophages can be pro- or anti-tumor, depending on the signals they receive. They contribute to tumor progression, metastasis, and the tumor microenvironment (TME), which is characterized by acidosis and metabolic changes. Macrophages can be influenced by various factors, including cytokines, chemokines, and exosomes, which shape their function and promote immune evasion. The plasticity of macrophages is crucial in cancer, with their ability to adapt to the TME and influence tumor progression. Understanding the molecular mechanisms underlying macrophage plasticity, including epigenetic regulation, microRNA expression, and metabolic changes, is essential for developing therapeutic strategies to combat cancer and other diseases.