Chronic rejection is a principal cause of long-term graft failure in solid organ transplantation. Characterized by progressive fibrotic remodeling, chronic rejection results from complex interactions among alloimmune responses, persistent inflammation, and dysregulated tissue repair mechanisms. This chapter provides a comprehensive overview of the cellular and molecular mechanisms underlying chronic rejection, with a focus on the roles of innate immune cells, T and B lymphocytes, profibrotic cytokines, signaling pathways, and extracellular matrix remodeling. A detailed mechanistic understanding of these pathways is critical for the identification of novel biomarkers and the development of targeted therapeutic strategies to prevent or ameliorate chronic rejection, thereby improving long-term graft survival.