Allogeneic hematopoietic stem cell transplantation is a potentially curative therapy for many malignant and non-malignant hematological diseases. Unfortunately, naïve donor T cells that are critical for the success of this effective therapy also cause its most severe toxicity--graft-versus-host disease (GVHD). Recent experimental observations have brought into focus a critical role for additional cell populations in the pathogenesis and modulation of GVHD. A better understanding of the complex interactions involving these cellular subsets and the inflammatory cascades is likely to be critical in the pathophysiology of GVHD. This review will primarily focus on the immunobiology of experimental acute GVHD with an emphasis on the recent observations on the novel role of innate and adaptive cellular subsets in the activation, effector phases, and target organ specificity of acute GVHD.