Chronic graft-versus-host disease (cGVHD) is a common complication after hematopoietic-cell transplant and remains the leading cause of late non-relapse mortality. Standard treatment includes a combination of a calcineurin inhibitor and corticosteroids. Prolonged steroid use is required, with more than 50% of patients continuing immunosuppression beyond 2 years. There is no standard second-line therapy for cGVHD. Many agents have been reported in small case series, but the studies are heterogeneous in patient selection and response criteria. There is a need for a systematic study of agents for secondary therapy of cGVHD. In addition, both cGVHD and its treatment are associated with severe complications, including life-threatening infections, reduced quality of life, and psychosocial disturbances. A multidisciplinary approach to evaluating and managing patients with cGVHD is preferred, and disciplined, prospective study of new therapies is essential to make further progress in its understanding and treatment.