Chronic graft-versus-host disease (GVHD) commonly occurs after allogeneic hematopoietic cell transplantation (HCT) despite standard prophylactic immune suppression. Intensified universal prophylaxis approaches are effective but risk possible over-treatment and may interfere with the graft-vs-malignancy immune response.We summarize conceptual and practical considerations regarding preemptive therapy of chronic GVHD, namely interventions applied after HCT based on evidence that the risk of developing chronic GVHD is higher than previously appreciated. This risk may be anticipated by clinical factors or risk assignment biomarkers or may be indicated by early signs and symptoms of chronic GVHD that do not fully meet NIH diagnostic criteria. However, truly preemptive, individualized, and targeted chronic GVHD therapies currently do not exist.The goals of this report are to (1) review current knowledge regarding clinical risk factors for chronic GVHD; (2) review what is known about chronic GVHD risk assignment biomarkers; (3) examine how chronic GVHD pathogenesis intersects with available targeted therapeutic agents; and (4) summarize considerations for preemptive therapy for chronic GVHD, emphasizing trial development including trial design and statistical considerations.We conclude that robust risk assignment models that accurately predict chronic GVHD after HCT and early phase preemptive therapy trials represent the most urgent priorities to advance this novel area of research.