The cells of an organism are constantly exposed to conflicting environmental cues that signal cell survival or cell death. Survival signals are delivered by autocrine or paracrine factors that actively suppress a default death pathway. This default death pathway appears to be activated by dedicated death receptors such as Fas, the TRAIL-receptors and other tumor necrosis factor receptor superfamily proteins (TNFR SFPs). Our understanding of how these counteracting receptor systems are modulated during tumorigenesis is only moderate. Nevertheless, there is now broad evidence that susceptibility of tumor cells towards Fas-mediated apoptosis is largely reduced. In addition, tumor cells frequently exhibit de novo expression of Fas-ligand (FasL) which plays a significant role in local tissue destruction, metastatic spread and immune escape of the tumor cells. Restoring the apoptotic potential of cancer cells upon modulating the expression and activity of certain key components of the cell death machinery is an attractive and obvious therapeutic anti-cancer strategy.