Tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptotic cell death in a variety of tumor cells by engaging the death receptors DR4 and DR5, while sparing most normal cells. Preclinical studies in mice and non‐human primates have shown the potential utility of recombinant soluble TRAIL and agonistic anti‐DR5 or DR4 antibodies for cancer therapy. Moreover, we have recently revealed a vital role for endogenously expressed TRAIL in immunosurveillance of developing and meta‐static tumors. In this review, we summarize recent knowledge about TRAIL and its receptors as promising targets for cancer therapy.