<p>Inflammatory memory enables cells to remember prior inflammatory signals, shaping their responses to subsequent challenges. While this phenomenon has been extensively characterized in immune cells and various tissues, recent reports suggest that both immune and nonimmune cells in the central nervous system (CNS) also exhibit inflammatory memory. In this Perspective, we synthesize emerging evidence of inflammatory memory in the CNS and discuss its underlying mechanisms. We highlight how epigenomic reprogramming through histone and DNA modifications, the recruitment of epigenetic regulators and nucleosome remodeling drive changes in gene expression kinetics central to inflammatory memory. We also examine mechanisms that maintain or reset inflammatory memory. By identifying shared principles and CNS-specific features, we propose conceptual frameworks to advance our understanding of CNS inflammatory memory and its implications for health and disease.</p>