Graft-versus-host disease (GVHD) is a serious complication of hematopoietic stem cell transplantation. The main clinical targets of GVHD are the skin, liver, gastrointestinal tract, and possibly the lung. The standard initial therapy for GVHD includes the use of high-dose steroids, which result in an unsatisfactory complete response (CR) rate of about 40% and the need to develop more effective therapies. The Clinical Trial Network is conducting a four-arm randomized phase II study evaluating prednisone in combination with one of the following four agents: etanercept, mycophenolate mofetil, denileukin diftitox, and pentostatin. Etanercept, an anti-TNF-alpha antibody, is also being evaluated in combination with steroids in a single-center phase II trial at the University of Michigan because of the role of TNF-alpha in the pathogenesis of GVHD. TNF-alpha and a surrogate marker, soluble TNF receptor, are elevated in patients with GVHD as early as 7 days after transplantation and maybe used in the future as a prognostic tool to identify transplant recipients at risk for developing GVHD.