Microglia, the innate immune cells of the central nervous system (CNS), play a crucial role in debris clearance, which is essential for both homeostasis and regeneration. Under normal conditions, microglia maintain CNS health through high motility and constant phagocytic activity, clearing cell debris and maintaining tissue integrity. Following injury, microglial phagocytic activity is amplified, facilitating the reorganization of neuronal circuits and triggering repair processes. Recent evidence suggests that this phagocytic clearance is more than just a cleanup function; it is a fundamental process that creates a pro-regenerative environment within the CNS. Insufficient debris clearance, often observed in neurodegenerative diseases and with aging, leads to inadequate regenerative responses. Understanding the mechanisms and functional significance of microglial-mediated debris clearance may open new therapeutic avenues for CNS injuries and diseases. Key phagocytic receptors, such as TREM2 and complement receptors, are essential for this process, and their dysfunction can contribute to chronic degenerative conditions. The efficient clearance of myelin debris is particularly important for remyelination and axon regeneration, and the presence of these receptors is crucial for successful regeneration in both experimental models and clinical settings.Microglia, the innate immune cells of the central nervous system (CNS), play a crucial role in debris clearance, which is essential for both homeostasis and regeneration. Under normal conditions, microglia maintain CNS health through high motility and constant phagocytic activity, clearing cell debris and maintaining tissue integrity. Following injury, microglial phagocytic activity is amplified, facilitating the reorganization of neuronal circuits and triggering repair processes. Recent evidence suggests that this phagocytic clearance is more than just a cleanup function; it is a fundamental process that creates a pro-regenerative environment within the CNS. Insufficient debris clearance, often observed in neurodegenerative diseases and with aging, leads to inadequate regenerative responses. Understanding the mechanisms and functional significance of microglial-mediated debris clearance may open new therapeutic avenues for CNS injuries and diseases. Key phagocytic receptors, such as TREM2 and complement receptors, are essential for this process, and their dysfunction can contribute to chronic degenerative conditions. The efficient clearance of myelin debris is particularly important for remyelination and axon regeneration, and the presence of these receptors is crucial for successful regeneration in both experimental models and clinical settings.