The apoptosis-inducing Fas receptor has been shown to be down-regulated in various types of tumors, while its ligand (FasL) appears to be frequently up-regulated. Here we provide evidence that there is a strong selective pressure in vivo against Fas-expressing, tumorigenic NIH3T3 cells, favoring survival, proliferation and eventually tumor formation by Fas-negative cells. Importantly, re-expression of Fas in these cells results in either the complete abolishment of tumor development, or in a significant extenuation of the latency period of tumor outgrowth. In addition, we found that environmental conditions which prevail during tumorigenesis, such as limiting amounts of survival factors and the lack of cell adhesion, are markedly sensitizing tumor cells to Fas-mediated suicide. Our data suggest that in addition to T cell-mediated immune responses, mechanisms of Fas-dependent tissue turnover are also centrally implicated in tumor cell clearance.