With the increasing use of mismatched, unrelated, and granulocyte colony-stimulating factor-mobilized peripheral blood stem cell donor grafts and successful treatment of older recipients, chronic graft-versus-host disease (cGVHD) has emerged as the major cause of non relapse mortality and morbidity. cGVHD is characterized by lichenoid changes and fibrosis that affects a multitude of tissues, compromising organ function. Beyond steroids, effective treatment options are limited. Thus, new strategies to both prevent and treat disease are urgently required. Over the last 5 years, our understanding of cGVHD pathogene-sis and basic biology, born out of a combination of mouse models and correlative clinical studies, has radically improved. We now understand that cGVHD is initiated by naive T cells, differentiating predominantly with in highly inflammatory T-helper 17/T-cytotoxic 17 and T-follicular helper paradigms with consequentthymic damage and impaired donor antigen presentation in the periphery. This leads to aberrant T- and B-cell activation and differentiation, which cooperate to generate antibody-secreting cells that cause the deposition of antibodies to polymorphic recipient antigens (ie, alloantibody) or nonpolymorphic antigens common to both recipient and donor (ie, autoantibody). It is now clear that alloantibody can, in concert with colony-stimulating factor 1 (CSF-1)-dependent donor macrophages, induce a transforming growth factor β-high environment locally within target tissue that results in scleroderma and bronchiolitis obliterans, diagnostic features of cGVHD. These findings have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition. This new understanding of cGVHD finally gives hope that effective therapies are imminent for this devastating transplant complication.