<p>Graft-versus-host disease (GVHD) remains a major barrier to successful allogeneic hematopoietic stem cell transplantation, and its prevention requires not only suppression of early alloimmune responses but also the rational design of post-transplant immune reconstitution. The pathophysiology of GVHD has traditionally been understood based on Billingham’s classical three criteria and a subsequent cytokine storm-driven, multistep model that emphasizes early tissue injury. In recent years, however, emerging concepts—including disruption of tissue tolerance in target organs and the layered reconstitution of donor T cells after transplantation, characterized by dynamic changes in fitness and exhaustion—have led to a refinement of these classical frameworks. This review summarizes recent advances, focusing on two key aspects: (1) updated local pathophysiological mechanisms, including injury to tissue stem cells and impaired regenerative capacity in target organs, disruption of the gut microbiota-metabolic network, and damage to the bone marrow hematopoietic niche; and (2) the mechanistic links between immune reconstitution and the development of acute and chronic GVHD, based on recent studies of donor T cell clonal dynamics. These insights support a shift from a unidimensional, immunosuppression-centered approach toward a novel, multidimensional therapeutic strategy that integrates organ protection, hematopoietic niche repair, and precise control of immune reconstitution.</p>