Graft-versus-host disease is the major complication after allogeneic hemopoietic stem cell transplantation. Graft-versus-host disease is destructive by itself and sets the stage for other sequelae, in particular overwhelming infections. Recent investigations, predominantly in murine models, have improved our understanding of the underlying pathophysiology. There are now compelling data on the role of host tissue destruction as the initial insult, extensive interactions of cellular donor and host components, a complex network of cytokines including interleukin-1, -2, -10, -11, -12, and -15, tumor necrosis factor-&agr;, interferon-γ, and ligands and receptors such as Fas/Fas-ligand, CD40/CD40L, CD28, CTLA-4, adhesion molecules, and other components in the development of graft-versus-host disease. The improved understanding of interactions between various signals is likely to allow for new prophylactic strategies. Numerous agents developed in experimental models are finding their way into clinical trials. There may be a need for new design structures in prophylactic and therapeutic trials that take into consideration individual donor and host characteristics as well as the kinetics of graft-versus-host disease development.