The study investigates the natural tumor surveillance capabilities of the host in six different mouse tumor models, focusing on the role of endogenous interleukin (IL)-12 in the efficiency of the innate immune response. Gene-targeted and lymphocyte subset-depleted mice were used to assess the importance of natural killer (NK) cells and NK1.1+ T (NKT) cells in protecting against tumor initiation and metastasis. In models where control of major histocompatibility complex class I-deficient tumors was independent of IL-12, CD3− NK cells were responsible for tumor rejection and protection from metastasis. A protective role for NKT cells was observed only when tumor rejection required endogenous IL-12 activity. Specifically, T cell receptor Jα281 gene-targeted mice confirmed the critical function of NKT cells in protecting against spontaneous tumors initiated by the chemical carcinogen, methylcholanthrene. This is the first report of an antitumor function for NKT cells in the absence of exogenously administered stimulators such as IL-12 or α-galactosylceramide. The findings highlight the importance of NKT cells in natural immune responses to spontaneous tumors and suggest that they may play a crucial role in protecting against more immunogenic tumors.The study investigates the natural tumor surveillance capabilities of the host in six different mouse tumor models, focusing on the role of endogenous interleukin (IL)-12 in the efficiency of the innate immune response. Gene-targeted and lymphocyte subset-depleted mice were used to assess the importance of natural killer (NK) cells and NK1.1+ T (NKT) cells in protecting against tumor initiation and metastasis. In models where control of major histocompatibility complex class I-deficient tumors was independent of IL-12, CD3− NK cells were responsible for tumor rejection and protection from metastasis. A protective role for NKT cells was observed only when tumor rejection required endogenous IL-12 activity. Specifically, T cell receptor Jα281 gene-targeted mice confirmed the critical function of NKT cells in protecting against spontaneous tumors initiated by the chemical carcinogen, methylcholanthrene. This is the first report of an antitumor function for NKT cells in the absence of exogenously administered stimulators such as IL-12 or α-galactosylceramide. The findings highlight the importance of NKT cells in natural immune responses to spontaneous tumors and suggest that they may play a crucial role in protecting against more immunogenic tumors.