For more than two decades, there has been a concerted effort to define the biology of, and develop the clinical applications for, cytokines that influence the immune system. However, intrinsic potency and toxicity have complicated application of cytokines as therapeutic agents when applied systemically. Indeed, one of the major characteristics of most cytokines is that they regulate immunity at a local or regional level, and systemic levels provided by most conventional schema fail to mimic the induction of an effective immune response. IL-4 has pleiotropic effects on immune cells of multiple lineages, endothelial cells and tumor cells. Accumulating data in pre-clinical studies demonstrate that sustained expression of IL-4 at the targeted organs or tissues may provide an effective means for therapy of variety of diseases including cancers and immunologic disorders. This review discusses biological properties and therapeutic applications of IL-4, particularly when it is delivered as a transgene in the settings of gene therapy.