Multiple cell-autonomous mechanisms exist in complex metazoans to resist oncogenic transformation, including a variety of tumor- suppressor pathways that control cell proliferation and apoptosis. In vertebrates, additional mechanisms of tumor resistance could potentially rely on cancer cell elimination by specialized cytotoxic leukocytes, such as natural killer (NK) cells. Such mechanisms would require that cancer cells be reliably distinguished from normal cells. The ligands for NKG2D, an activating NK cell receptor, are expressed on many tumor cell lines and at least some primary human tumors. However, it is unknown whether their expression is induced as a direct result of oncogenic transformation in vivo. We provide evidence that NKG2D ligands are induced on spontaneously arising tumors in a murine model of lymphomagenesis and that c-Myc is involved in their regulation. Expression of NKG2D ligands is induced at an early, distinct stage of tumorigenesis upon acquisition of genetic lesions unique to cancer cells, potentially defining a critical step in carcinogenesis. This finding suggests that the regulation of NKG2D ligands depends on a mechanism for intrinsic sensing of oncogenic transformation.