This review addresses pitfalls of clinical trials to evaluate new approaches for prevention or treatment of graft-versus-host disease. Determination of end points poses a difficult challenge in the design of clinical trials, and examples from previous studies are used to illustrate some of the pitfalls. Also discussed is the need for a new conceptual approach for evaluation of graft-versus-host disease after non-myeloablative conditioning regimens, because the donor anti-recipient alloimmune reaction is the primary mechanism of benefit with this type of treatment. Finally, investigators should be aware of regulatory and socioeconomic pitfalls that apply to all clinical trials.