This study investigates the role of natural killer (NK) and NKT cells in tumor surveillance in six different mouse tumor models, where endogenous interleukin (IL)-12 either facilitates or does not facilitate the innate immune response. The research uses gene-targeted and lymphocyte subset-depleted mice to determine the relative importance of NK and NKT cells in protecting against tumor initiation and metastasis. In models where control of MHC class I-deficient tumors is independent of IL-12, CD3- NK cells are responsible for tumor rejection and protection from metastasis. NKT cells, however, only play a protective role when tumor rejection requires endogenous IL-12 activity. T cell receptor Jα281 gene-targeted mice confirmed a critical function for NKT cells in protection from spontaneous tumors initiated by the chemical carcinogen, methylcholanthrene. This is the first description of an antitumor function for NKT cells in the absence of exogenous stimulators such as IL-12 or α-galactosylceramide. The study highlights the distinct roles of NK and NKT cells in tumor surveillance, with NK cells being crucial in IL-12-independent tumor control, while NKT cells are essential in IL-12-dependent scenarios. The findings suggest that NKT cells contribute to tumor surveillance through direct lysis of tumor cells, particularly in the absence of exogenous stimuli. The study also indicates that NK cells may play a role in tumor surveillance, but their contribution is not as critical as that of NKT cells in certain models. The results emphasize the importance of both NK and NKT cells in the innate immune response against tumors, with NKT cells playing a key role in IL-12-mediated antitumor activity. The study provides new insights into the natural tumor surveillance capabilities of NKT cells and their potential therapeutic applications in cancer treatment.This study investigates the role of natural killer (NK) and NKT cells in tumor surveillance in six different mouse tumor models, where endogenous interleukin (IL)-12 either facilitates or does not facilitate the innate immune response. The research uses gene-targeted and lymphocyte subset-depleted mice to determine the relative importance of NK and NKT cells in protecting against tumor initiation and metastasis. In models where control of MHC class I-deficient tumors is independent of IL-12, CD3- NK cells are responsible for tumor rejection and protection from metastasis. NKT cells, however, only play a protective role when tumor rejection requires endogenous IL-12 activity. T cell receptor Jα281 gene-targeted mice confirmed a critical function for NKT cells in protection from spontaneous tumors initiated by the chemical carcinogen, methylcholanthrene. This is the first description of an antitumor function for NKT cells in the absence of exogenous stimulators such as IL-12 or α-galactosylceramide. The study highlights the distinct roles of NK and NKT cells in tumor surveillance, with NK cells being crucial in IL-12-independent tumor control, while NKT cells are essential in IL-12-dependent scenarios. The findings suggest that NKT cells contribute to tumor surveillance through direct lysis of tumor cells, particularly in the absence of exogenous stimuli. The study also indicates that NK cells may play a role in tumor surveillance, but their contribution is not as critical as that of NKT cells in certain models. The results emphasize the importance of both NK and NKT cells in the innate immune response against tumors, with NKT cells playing a key role in IL-12-mediated antitumor activity. The study provides new insights into the natural tumor surveillance capabilities of NKT cells and their potential therapeutic applications in cancer treatment.