The MI and M2 paradigm of macrophage activation has been widely used to classify macrophage functional states, but recent research suggests that this model is outdated and needs reassessment. Macrophages respond to a variety of stimuli, including cytokines, pathogens, and immune products, leading to diverse functional phenotypes. The traditional dichotomy of classical (MI) and alternative (M2) activation, based on Th1 and Th2 cytokines, has been criticized for oversimplifying the complexity of macrophage responses. New evidence indicates that macrophage activation is a dynamic process influenced by multiple factors, including cytokines, receptors, and signaling pathways. The current model fails to account for the context of stimuli, the diversity of macrophage subsets, and the plasticity of their functions. Recent studies have shown that macrophages can exhibit mixed activation states and that their functions are not strictly divided into MI or M2. The authors propose a more nuanced understanding of macrophage activation, emphasizing the need to consider the complex interactions between different stimuli and the dynamic nature of macrophage responses. This approach would better reflect the diversity of macrophage functions in various physiological and pathological conditions. The review highlights the importance of integrating new findings from immunology, genetics, and functional studies to develop a more accurate and comprehensive model of macrophage activation.The MI and M2 paradigm of macrophage activation has been widely used to classify macrophage functional states, but recent research suggests that this model is outdated and needs reassessment. Macrophages respond to a variety of stimuli, including cytokines, pathogens, and immune products, leading to diverse functional phenotypes. The traditional dichotomy of classical (MI) and alternative (M2) activation, based on Th1 and Th2 cytokines, has been criticized for oversimplifying the complexity of macrophage responses. New evidence indicates that macrophage activation is a dynamic process influenced by multiple factors, including cytokines, receptors, and signaling pathways. The current model fails to account for the context of stimuli, the diversity of macrophage subsets, and the plasticity of their functions. Recent studies have shown that macrophages can exhibit mixed activation states and that their functions are not strictly divided into MI or M2. The authors propose a more nuanced understanding of macrophage activation, emphasizing the need to consider the complex interactions between different stimuli and the dynamic nature of macrophage responses. This approach would better reflect the diversity of macrophage functions in various physiological and pathological conditions. The review highlights the importance of integrating new findings from immunology, genetics, and functional studies to develop a more accurate and comprehensive model of macrophage activation.