Developing effective and safe therapies for cancer continues to be a primary objective of both basic researchers and clinicians. However, despite evidence of progress in treating specific tumors, in many instances, especially in the context of metastasis, no effective therapies are available. A focus of our laboratories is to develop improved cancer therapeutics that exploit differences in signaling pathways and gene expression in tumor versus normal cells. An approach, which we have pioneered, is the use of differentiation therapy combined with subtraction hybridization, DISH (differentiation induction subtraction hybridization), to define genes that are relevant to cancer growth control, differentiation and apoptosis. Application of DISH to human melanoma cells permitted the cloning of melanoma differentiation associated (mda) genes that display elevated expression as a function of induction of terminal differentiation and loss of tumorigenic potential in cancer cells. One mda gene, mda-7, has emerged as a potential therapeutic for cancer because of its unique ability to selectively induce apoptosis in cancer cells, without affecting normal cells. Based on structure, location and properties, mda-7, a cytokine belonging to the IL-10 family, is now designated as IL-24. mda-7/IL-24 exhibits multiple levels of anti-cancer effects that include inhibition of angiogenesis, radiosensitization and potent antitumor bystander activities. As a cytokine it also demonstrates immunostimulatory properties. An adenovirus expressing mda-7/IL- 24, INGN 241, has entered the clinic and been shown to be safe and display significant activity toward solid tumors, including melanoma, in a Phase I clinical trial. We presently provide a brief overview of mda-7/IL-24.