Induction of apoptosis in tumor cells by death receptor activation is a novel therapeutic strategy. However, in systemic antitumor treatments, severe toxic effects have been observed with tumor necrosis factor-alpha (TNF-alpha) and CD95 ligand. TNF-alpha causes a lethal inflammatory response and CD95L produces lethal liver damage. Preclinical studies in mice and nonhuman primates showed no systemic cytotoxicity upon injection of recombinant TNF-related apoptosis-inducing ligand (TRAIL) at doses that effectively suppressed solid tumors such as colon and mammary carcinomas. Although unwanted effects of some TRAIL preparations have been reported in normal cells, these data suggest that TRAIL could be a suitable approach in cancer therapy. However, several mechanisms of resistance to TRAIL-mediated apoptosis have been described in tumor cells such as lack of TRAIL apoptotic receptors, enhanced expression of TRAIL-decoy receptors, and expression of apoptosis inhibitors. In combination regimes, interferon-gamma (IFN-gamma) could provide a promising antitumor therapeutic approach as it has been described to enhance cellular susceptibility to apoptosis in a variety of tumor cells. The mechanism by which IFN-gamma promotes cell death seems to be via the regulation of the expression of different proteins involved in apoptosis. Altogether, these data suggest a combination strategy to selectively kill tumor cells that need to be further explored.