Abstract Cancers are distributed unevenly across the body, suggesting that cell context dictates susceptibility to transformation. To test this hypothesis, we mapped cellular susceptibility to tumor initiation across all organs in adult mice. Ten combinations of potent oncogenic mutations, including activating mutations of Kras, Notch1, Ctnnb1 and deletions of tumor suppressors Tp53,Pten and Cdkn2a, were targeted by conditional recombination into Prom1+ (CD133+) cells in the organs of >800 Prom1-Cre/+ mice. Life time clinical surveillance, necropsy and gene expression profiling of over 250 animals, across all genotypes, identified extensive tumor formation that was biased to certain organs including small intestine, stomach, liver, skin, prostate and uterus. Extensive histology and cross-species genomics confirmed these tumors recapitulated >250 tissue-matched human cancers. Detailed mapping of the number and proliferative activity of Prom1+ cells in organs demonstrated that these variables did not dictate cancer incidence. Rather, parallel, life-long linage tracing of Prom1+ populations showed that the capacity of these cells to repair and regenerate their host organ is directly correlated with their tumorigenic capacity. Only Prom1+ cells capable of long-term tissue renewal generated cancers; quiescent and differentiated Prom1+ cells rarely formed tumors regardless of targeted oncogenic mutation. The repair/regeneration capacity of Prom1+ populations also dictated developmental and damage-response patterns of tumorigenesis. Normally quiescent and tumor-resistant Prom1+ cells in the adult liver became highly regenerative upon liver damage, dramatically increasing their tumorigenic capacity. Conversely, Prom1+ cells are highly proliferative in the neonatal liver - driving the development of this organ - and were highly susceptible to transformation without inducing liver damage. Remarkably, neonatal Prom1+ cells formed hepatoblastoma, the pediatric form of liver cancer. Our large-scale, comprehensive mapping of tumor susceptibility shows that cell ground-state, and specifically the capacity to repair and regenerate organs, is a common determinant of cancer susceptibility across all major organs. Citation Format: Liqin Zhu, Helen Poppleton, Geoffrey Neale, Arzu Onar-Thomas, Stanley Pounds, Armita Bahrami, Sarah Utley, Kasper S. Wang, Dolores H. Lopez-Terrada, David W. Ellison, Richard J. Gilbertson. Cell ground state dictates cancer susceptibility across organs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-63. doi:10.1158/1538-7445.AM2014-LB-63