Graft vs. host disease (GVHD) is the major non-relapse complication associated with allogeneic hematopoietic stem cell transplantation (HSCT). Damage to the gastrointestinal (GI) tract from acute GVHD is a particularly serious event that can result in significant morbidity and mortality. Proinflammatory cytokines play a critical role in the pathophysiology of intestinal GVHD, in part by activating donor T cell populations which subsequently induce tissue damage. In this review, we summarize pre-clinical data derived from experimental murine models that have examined the role of inflammatory cytokine pathways that play critical roles in the pathophysiology of GVHD of the GI tract. Specific areas of focus are on STAT 3-dependent cytokines (e.g., IL-6, IL-23, and IL-21), and members of the IL-1 cytokine family, both of which have been shown to induce pathological damage within the GI tract during this disease. We also review established and ongoing efforts to translate these pre-clinical findings into the clinic in an effort to reduce morbidity and mortality due to this complication.