There have been many advances in the prevention and treatment of GVHD, including cyclosporine, FK506, and combination therapies. This syndrome, however, continues to account for significant morbidity and mortality after allogeneic transplantation. With the expanded use of matched unrelated as well as mismatched related donors, the increase in incidence and severity of GVHD poses a new clinical challenge. Many of the newer agents discussed in this paper may have a role in the future as therapy for acute GVHD. The evaluation of these new agents and the approach to be taken is hampered by the realization that most patients have received and are relatively refractory to standard therapies. Clinical trials must be performed earlier in the course of the syndrome to establish the role of these compounds. Newer strategies are likely to include the use of sequential therapy directed at blocking endogenous cytokines followed by blocking alloreactive donor cells, and immunologic advances such as the induction of tolerance. What impact, if any, such therapy may have on amelioration of a graft-versus-leukemia effect remains unknown.