The pathophysiology of acute graft versus host disease (GVHD) can be considered as a three-step process where the innate and adaptive immune systems interact (Fig. 1). The three steps are: 1) tissue damage to the recipient by the radiation/chemotherapy pre-transplant conditioning regimen, 2) donor T cell activation and clonal expansion, and 3) cellular and inflammatory factors. This schema underscores the importance of mononuclear phagocytes and other accessory cells to the development of GVHD after complex interactions with cytokines secreted by activated donor T cells. In step 1, the conditioning regimen (irradiation and/or chemotherapy) leads to damage and activation of host tissues throughout the body and the secretion of inflammatory cytokines Tumor Necrosis Factor (TNFα) and Interleukin (IL-1). These cytokines may enhance donor T cell recognition of host alloantigens by increasing expression of major histocompatibility complex (MHC) antigens and other molecules on host antigen presenting cells (APCs). Inflammatory cytokines may also stimulate chemokine release, recruiting donor T cells into host target organs. In step 2, host APCs present alloantigen (an HLApeptide complex) to the donor T cells. Co-stimulatory signals are required for T cell activation and these signals further activate APCs which in turn enhance T cell stimulation, characterized by cellular proliferation and the secretion of cytokines. IL-2 expands the T cell clones and induces cytotoxic T cell (CTL) responses; whereas, IFNγ has multiple effects, including the priming of mononuclear phagocytes to produce TNFα and IL-1. In step 3, effector functions of mononuclear phagocytes and neutrophils are triggered through a secondary signal provided by mediators such as lipopolysaccharides (LPS) that leak through the intestinal mucosa damaged during step 1. This inflammation, along with direct lysis of target cells by CTL, causes pathologic changes in target organs. Risk factors, as well as strategies to prevent GVHD, can be conceptualized according to this three-step model and will be reviewed in this article.