We have investigated the importance of endogenously produced IL‐12 in innate and adaptive immunity to tumor transplants. The immunogenic lymphoma RMA and its TAP‐deficient variant RMA‐S were tested for rejection responses by normal and IL‐12‐deficient mice. IL‐12 was crucial for the immunity induced by one immunization with irradiated RMA cells, as well as for in vivo priming of a CTL response in mixed lymphocyte tumor cultures against this MHC class I‐expressing tumor. The defective in vivo response could be overcome by multiple immunizations. In further studies of in vitro CTL responses, we found that IL‐12 production from either the antigen‐pulsed dendritic cells or from host cells was necessary to obtain strong CTL responses. In the complete absence of IL‐12, no or only very weak responses could be detected. NK cell‐mediated innate resistance, as assessed in non‐immunized mice inoculated with a threshold dose of RMA‐S cells, also required IL‐12. However, NK cells with reduced activity were present in IL‐12‐deficient mice and contributed to innate resistance, as demonstrated with lower cell dose challenges. In conclusion, IL‐12 is required for optimal adaptive and innate responses against tumors.