In the 1970s and 1980s, GVHD prevention approaches were limited in number. Recent advances in our understanding of the requirements for T-cell immune responses and for basic mechanism(s) involved in GVHD pathophysiology have led to exciting new strategies for GVHD prevention. This review focuses upon recent developments in GVHD prevention generated over the past 5 years. We have selected five different types of strategies to highlight including: 1) the in vivo targeting of GVHD-reactive T cells using either intact and F(ab')2 fragments of monoclonal antibodies directed against T-cell-surface determinants or immunotoxins which consist of antibodies linked to toxins, 2) a comparison of the in vivo immunosuppressive effects of FK506 and rapamycin on T-cell signaling, 3) the inhibition of T-cell activation through blockade of costimulatory or adhesogenic signals, 4) shifting the balance between acute GVHD-inducing T-helper-type 1 (Th1) T cells to anti-inflammatory T-helper-type 2 (Th2)-type T cells, and 5) the regulation of alloreactive T-cell activation by treatment with peptide analogs which affect either TCR/MHC, CD4/MHC class II, or CD8/MHC class I interactions. Collectively, these approaches are illustratrative of the progress made in extending our GVHD prevention armamentarium.