Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines and has been shown to induce cell death in many types of tumor and transformed cells but not in normal cells. This tumor-selective property has made TRAIL a promising candidate for the development of cancer therapy. However, safety issues are a concern because certain preparations of recombinant TRAIL protein were reported to induce toxicity in normal human hepatocytes in culture. In addition, previous studies on tumor selectivity of exogenous TRAIL protein were carried out in xenograft models, which do not directly address the tumor selectivity issue. It was not known whether exogenous or overexpression of TRAIL in a syngeneic system could induce tumor cell death while leaving normal tissue cells unharmed. Thus, the tumor selectivity of TRAIL-induced apoptosis remains to be further characterized. In our study, we established mice that overexpress TRAIL by retroviral-mediated gene transfer in bone marrow cells followed by bone marrow transplantation. Our results show that TRAIL overexpression is not toxic to normal tissues, as analyzed by hematologic and histologic analyses of tissue samples from TRAIL-transduced mice. We show for the first time that TRAIL overexpression in hematopoietic cells leads to significant inhibition of syngeneic tumor growth in certain tumor lines. This approach may be used further to identify important molecules that regulate the sensitivity of tumor cells to TRAIL-induced cell death in vivo. (Cancer Res 2006; 66(12): 6304-11)