Clinical outcomes for patients undergoing allogeneic hematopoietic stem cell transplantation continue to improve, but chronic graft-versus-host disease (GVHD) remains a common toxicity and major cause of nonrelapse morbidity and mortality. Treatment of chronic GVHD has previously relied primarily on corticosteroids and other broadly immune suppressive agents. However, conventional immune suppressive agents have limited clinical efficacy in chronic GVHD, and prolonged immune suppressive treatments result in additional toxicities that further limit clinical recovery from transplant and return to normal daily function. Recent advances in our understanding of the immune pathology of chronic GVHD offer the possibility that new therapeutic approaches can be directed in more precise ways to target specific immunologic mechanisms and pathways. In this review, we briefly summarize current standard treatment options and present new therapeutic approaches that are supported by preclinical studies and early-phase clinical trials suggesting that these approaches may have clinical utility for treatment or prevention of chronic GVHD. Further evaluation of these new therapeutic options in well-designed prospective multicenter trials are needed to identify the most effective new agents and improve outcomes for patients with chronic GVHD.