The TNF-related apoptosis-inducing ligand (TRAIL) offers great promise as a cancer therapeutic. Initially, soluble recombinant versions of the TRAIL molecule have exhibited specific tumoricidal activity against a variety of tumors alone, or in combination with other cancer treatments, and much anticipation awaits the outcomes from early clinical trials. More recently, the natural role of TRAIL has been explored in tumor and allogeneic bone marrow transplantation models in the mouse. Strikingly, the TRAIL effector pathway appears a vital component of immunosurveillance of spontaneous or resident tumor cells by both T cells and NK cells, stimulating more hope that manipulating TRAIL activity is a natural path to improved cancer immunotherapy.