The ability of oncogenes to engage tumor suppressor pathways represents a key regulatory mechanism that can limit the outgrowth of incipient tumor cells. For example, in a number of settings oncogenic Ras strongly activates the Ink4a/Arf locus, resulting in cell cycle arrest or senescence. The capacity of different cell types to execute tumor suppressor programs following expression of endogenous K-ras^G12D in vivo has not been examined. Using compound mutant mice containing the Arf^GFP reporter and the spontaneously activating K-ras^LA2 allele, we have uncovered dramatic tissue specificity of K-ras^G12D-dependent p19^Arf up-regulation. Lung tumors, which can arise in the presence of functional p19^Arf, rarely display p19^Arf induction. In contrast, sarcomas always show robust activation, which correlates with genetic evidence, suggesting that loss of the p19^Arf-p53 pathway is a requisite event for sarcomagenesis. Using constitutive and inducible RNAi systems in vivo, we highlight cell type-specific chromatin regulation of Ink4a/Arf as a critical determinant of cellular responses to oncogenic K-ras. Polycomb-group complexes repress the locus in lung tumors, whereas the SWI/SNF family member Snf5 acts as an important mediator of p19^Arf induction in sarcomas. This variation in tumor suppressor induction might explain the inherent differences between tissues in their sensitivity to Ras-mediated transformation.