SR/CR mice are capable of mounting a highly effective response of leukocytes to large doses of lethal transplantable mouse cancer cells. This response is conferred by a dominant, germline-transmissible mutation independent of sex chromosomes. The resistance can be extended to a broad array of mouse and human cancer cells without harming normal cells. The effector cells are primarily composed of the leukocytes from the innate immune system including macrophages, neutrophils, and natural killer cells. The mice are cancer-free and healthy without detectable abnormality or shortened life span. However, the immune response mechanism of these SR/CR mice is dramatically modulated by the aging process. In this article, we summarize the lessons learned from these mice and discuss possible implications of these findings in our understanding of the effects of aging on the immunity against cancer.