Interleukin-18 (IL-18) was first discovered as an interferon gamma-inducing activity in the blood of mice injected intraperitoneally first with Proprionibacterium acnes and again one week later with bacterial lipopolysaccharide. Using mainly the mouse Meth A sarcoma as a model, murine IL-18 was successfully used to elicit protective anti-tumor immune responses. These responses resulted in Meth A-specific immune memory in mice surviving intraperitoneal transplantation of the tumor. Step-by-step investigation of the mechanisms responsible for the anti-tumor effects of interleukin-18 revealed a cascade of immunological events characterized by the successive induction of anti-tumor NK cells, and CD4⁺ and CD8⁺ T cells. Neutralizing antibodies to the respective cellular sub-sets were able to abrogate various aspects of the anti-tumor immune response. Further kinetic analysis of the immunological cascade revealed a correlation between anti-tumor effector cell induction and distinct patterns of immunomodulatory cytokine production, in particular the productions of interleukin-10 and interleukin-2, by spleen cells isolated from treated tumor-bearing mice as compared to control, untreated tumor-bearing mice. The anti-tumor immunological events elicited by interleukin-18 reveal an immune network that is likely important for the successful induction of specific anti-tumor immunity and should help to identify cancer patients that are most likely to benefit from immunotherapy as well as serve as a model for the identification of therapeutic strategies