Chronic graft-versus-host disease (GVHD) occurs in recipients of allogeneic hematopoietic stem cell transplantation with a high frequency. Preclinical animal chronic GVHD models outlined in this chapter allow for the delineation of events that occur during chronic GVHD development. The DBA/2 → (C56BL/6 × DBA/2)F1 (BDF1) model is characterized by systemic lupus erythematosus (SLE)-like phenotype. The B10.D2 → Balb/c model presents many features of autoimmune scleroderma. The former model is useful in defining how alloreactive donor CD4⁺ T cells break B-cell tolerance, whereas the latter model is suitable for dissecting the pathogenesis of organ fibrosis. Our laboratory has demonstrated that injection of a single dose of strong CD137 agonists can prevent or cure chronic GVHD in these two models. In general, these models are particularly suited to screening the immunomodulatory therapeutics.