To become active and extracellularly released, IL-18 needs post-translational processing by the cytoplasmic enzyme caspase-1, which has high sequence homology with apoptotic cell death-associated enzymes in Caenorhabditis elegans. Furthermore, the receptor for IL-18 shares the signal transduction pathway with the Toll-like receptor, which highly resembles that for the host defense in Drosophila. Since nonvertebrates utilize only innate immunity, it is plausible that IL-18 is an innate immune cytokine. IL-18 is produced by both immune and nonimmune cells, and influences both immunity and nonimmune biology with dual functions beneficial for health and causative of diseases. In this review, recently identified features of IL-18 will be focused upon, followed by discussion of IL-18 as a possible therapeutic target.