The novel cytokine MDA-7/IL-24 was identified by subtractive hybridization in the mid-1990s as a cytokine whose expression increased during the induction of terminal differentiation, and that was either not expressed or was present at low levels in tumor cells compared to non-transformed cells. Multiple studies from several laboratories have subsequently demonstrated that expression of IL-24 in tumor cells, but not in non-transformed cells, causes their growth arrest and ultimately cell death. In addition, IL-24 has been noted to be a radiosensitizing cytokine, which in part is due to the generation of reactive oxygen species (ROS) and causing endoplasmic reticulum stress. Recent publications of Phase I trial data have shown that a recombinant adenovirus to express MDA-7/IL-24 (Ad.mda-7(INGN 241)) was safe and had tumoricidal effects in patients, which argues that IL-24 may have therapeutic value. This review describes what is known about the impact of IL-24 on tumor cell biology in addition to approaches that may enhance the toxicity of this novel cytokine.