Understanding the mechanisms by which T lymphocytes mediate antitumor activity in vivo may have important implications for the design of active, adoptive and combination immunotherapies against neoplastic progression. The Fas/Fas ligand (FasL) system utilized by antigen (Ag)-specific T cells has been now demonstrated to play important roles in lymphocyte-mediated tumor regression in vivo. However, the process of tumor eradication by Fas/FasL interactions per se may serve also as an immune-based selective pressure. Indeed, more recent studies have illustrated that this same Fas/FasL system may have negative contributions, perhaps serving as a novel mechanism of tumor escape of Fas-resistant subpopulations. In addition to Fas-resistance, functional FasL expression by certain cancer cell types has been implicated in tumor escape via destruction of infiltrating Fas-bearing lymphocytes. Thus, the acquisition of Fas-resistance by advancing neoplastic subpopulations, possibly in combination with FasL induction may serve as countermeasures against immune attack and contribute favorably toward metastatic development. Further appreciation of the complex nature of this Fas/FasL system, exploited not only by innate or adaptive elements of the immune response, but also by a developing neoplasm may have important implications for the regulation of tumor progression in favor of clinical regression. Thus, this review will focus on both positive and negative consequences of the Fas/FasL system during host/tumor interactions. Emphasis will be on the importance of the Fas/FasL pathway for antitumor activity, as well as a potential selective force influencing the escape of Fas-resistant aggressive tumor variants.