Despite significant progress in early cancer detection and aggressive therapies, effective treatments for metastatic disease frequently fall short of producing the desired effect of engendering a 'cure.' This can be attributed in part to inherent and acquired resistance of primary and evolving tumor cells to conventional therapeutic approaches. Agents that can interfere with critical aberrant cell signaling and survival pathways in tumor cells while displaying minimal or preferably no toxicity to normal cells represent potentially powerful tools for cancer therapy. A recently identified cancer gene therapeutic is melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) that has the unique ability of inducing apoptosis in diverse cancer cells without harming normal cells or tissues. As a secreted cytokine mda-7/IL-24 also exerts anti-angiogenic, radiosensitizing and immunomodulatory effects and the therapeutic benefits of an adenovirus expressing mda-7/IL-24 (Ad.mda-7) in human xenograft animal models has been successfully recapitulated in a Phase I clinical trial in patients with advanced cancers. However, as with most treatment modalities, particular subsets of tumor cells might be inherently resistant to mda-7/IL-24, as observed in pancreatic and specific colorectal cancer cells, or they might acquire resistance because of repeated exposure to this cytokine. Pataer et al. have developed Ad.mda-7-resistant lung cancer cells in vitro and demonstrated that the combination of Ad.mda-7 with bcl-2 siRNA or 17AAG could overcome this resistance. Indeed, previous studies have also demonstrated that combinatorial approaches employing Ad.mda-7 and diverse other modalities, such as chemo- or radiotherapy, small molecule inhibitors and monoclonal antibodies, can either augment the therapeutic effect of Ad.mda-7 or overcome resistance to this gene. In these contexts, should resistance to monotherapy with mda-7/IL-24 occur, combinatorial therapies with this cytokine might provide a viable path for potentially curing patients of primary and metastatic cancer.