Interleukin-18 (IL-18) is a proinflammatory cytokine in the IL-1 family that exerts distinct immune effects depending on the local cytokine environment. It is expressed as a 24 kDa precursor by endothelial and epithelial cells, keratinocytes, gamma δ T cells, and phagocytes. The precursor is activated intracellularly by Caspase-1 mediated proteolysis to release the 17 kDa mature cytokine. The precursor can also be released by necrotic cells for extracellular cleavage by multiple proteases. IL-18 activation is induced by infection or tissue damage and contributes to disease pathology in chronic inflammation. IL-18 binds to the widely expressedIL-18 R alpha which recruits IL-18 R beta to form the signaling receptor complex. Its bioactivity is negatively regulated by interactions with IL-18 binding proteins and virally encoded IL-18BP homologs. In the presence of IL-12 or IL-15, IL-18 enhances anti-viral Th1 immune responses by inducing IFN-gamma production and the cytolytic activity of CD8+ T cells and NK cells. In the absence of IL-12 or IL-15, however, IL-18 promotes production of the Th2 cytokines IL-4 and IL-13 by CD4+ T cells and basophils. In the presence of IL-1β or IL-23, IL-18 induces the antigen-independent production of IL-17 by gamma δ T cells and CD4+ T cells. IL-18 also promotes myeloid dendritic cell maturation and triggers neutrophil respiratory burst. In cancer, IL-18 exhibits diverse activities including enhancing anti-tumor immunity, inhibiting or promoting angiogenesis, and promoting tumor cell metastasis. Mature human IL-18 shares approximately 63% amino acid sequence identity with mouse and rat IL-18. Alternative splicing in human ovarian cancer generates an isoform that is resistant to Caspase-1 activation. A cell surface form can be expressed on M-CSF induced macrophages and released in response to bacterial endotoxin.