A hallmark in the pathogenesis of cancer is the increased expression of heat shock proteins (Hsps) and other molecular chaperones observed in many tumor types, which is considered to be an adaptive response to enhance tumor cell survival. Heat shock transcription factor 1 (Hsf1) is a major transactivator of Hsp induction and has been proposed to affect tumor initiation and progression, regulating expression of Hsps and other molecular targets. In this report, we provide direct in vivo evidence that Hsf1 plays a critical role in the evolution of spontaneous tumors arising in p53(-/-) mice. Thus, loss of Hsf1 function did not prolong tumor-free survival, but surprisingly altered the spectrum of tumors that arose in p53(-/-) mice. Tumor development is rapid in p53(-/-) mice, which predominantly (about 70%) succumb to lymphomas. In contrast, hsf1(-/-)p53(-/-) mice rarely develop lymphomas (<8%), but succumb to other tumor types including testicular carcinomas and soft tissue sarcomas. Our findings suggest that an increase in p53-independent apoptotic cell death in association with altered cytokine signaling and suppressed production of inflammatory factors in hsf1(-/-) mice may contribute to selective lymphoma suppression. In conclusion, the data presented here link the loss of Hsf1-dependent function to decreased susceptibility to spontaneous lymphomagenesis, which may have implications for cancer prevention and therapy.