Allogeneic stem cell transplantation (SCT) is an important therapy for a number of malignant diseases, and acute graft versus host disease (GVHD) and leukemic relapse remain the two major obstacles to successful outcomes of this treatment strategy. The therapeutic potential of allogeneic SCT relies on the graft versus leukemia (GVL) effect, during which donor T lymphocytes eradicate residual malignant cells via immunological mechanisms. Unfortunately, beneficial GVL effects are closely associated with the toxicity of GVHD. The pathophysiology of GVHD is complex and fundamentally depends upon aspects of adaptive immunity and interactions between donor T cells and foreign host tissue antigens. Recent work has revealed that components of the innate immune response and the secretion of inflammatory cytokine effectors are also important. In this context, experimental studies have demonstrated that loss of gastrointestinal (GI) tract integrity plays a major role in the amplification of systemic GVHD. Specifically, translocation of endotoxin across a damaged GI tract and into the circulation promotes local and systemic cytokine release. This effect perpetuates further gut mucosal injury and endotoxin leak, thus establishing a positive feedback loop for progressive target organ injury and systemic inflammation. Data obtained using murine SCT models have shown that disruption of the cellular activating effects of lipopolysaccharide (LPS) significantly reduces cytokine secretion and GVHD severity without altering T-cell responses to host antigens. These findings support a critical role for LPS in the early inflammatory events responsible for GVHD and suggest that strategies which target the innate immune response and LPS receptor-ligand interactions may help prevent GVHD while preserving donor T-cell responses and GVL activity.