Telomere maintenance is critical for cancer progression. To examine mechanisms of tumor suppression induced by short telomeres, we crossed mice deficient for the RNA component of telomerase, mTR(-/-), with Emu-myc transgenic mice, an established model of Burkitt's lymphoma. Short telomeres suppressed tumor formation in Emu-myc transgenic animals. Expression of Bcl2 blocked apoptosis in tumor cells, but surprisingly, mice with short telomeres were still resistant to tumor formation. Staining for markers of cellular senescence showed that pretumor cells induced senescence in response to short telomeres. Loss of p53 abrogated the short telomere response. This study provides in vivo evidence for the existence of a p53-mediated senescence mechanism in response to short telomeres that suppresses tumorigenesis.