Graft-versus-host disease (GVHD) has been the primary limitation to the wide application of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is initiated by activation of donor T cells recognizing host tissue antigens, with subsequent dysregulated inflammatory cytokine production by monocytes and macrophages. These inflammatory cytokines are crucial for the pathogenesis of acute GVHD and these inflammatory manifestations are recognized as clinical acute GVHD. This paper presents a brief review of the mechanisms underlying inflammatory cytokine responses during acute GVHD and various strategies aimed at the prevention of acute GVHD. As cytokines and growth factors that are protective against GVHD are also produced during inflammatory cytokine responses, the factors contributing to the protection against GVHD are also reviewed. Attention has focused on the mechanisms responsible for the protection against GVHD conferred by hepatocyte growth factor and sphingosin-1-phosphate, which are abundantly stored in platelets. These factors are produced during inflammation and tissue injury and regulate immune, hematopoietic and regenerative responses. Novel therapies aimed at protection against GVHD using protective growth factors are discussed, although in most cases, their clinical relevance has not been established. Carefully designed clinical trials are awaited to evaluate their usefulness in the prevention and management of GVHD.