The development of new drugs able to directly activate the apoptotic machinery in tumors is a promising approach in the treatment of cancer as it is independent of sensors and checkpoints, which are frequently mutated in cancer hampering current anti-proliferative chemotherapy. The Fas death receptor (CD95 or APO-1) conveys apoptotic signals through binding to its cognate ligand, FasL (CD95L). Unfortunately, the putative clinical antitumor action of FasL cannot be realized because of severe liver toxicity due to the high presence of Fas in hepatocytes. However, recent evidence for FasL-independent activation of Fas suggests that the death receptor can also be activated intracellularly, in the absence of its ligand. Unraveling the mechanisms that underlie the intracellular activation of Fas can provide the basis for novel therapeutic strategies and for the development of new compounds able to exploit cytoplasmic triggers of apoptosis. This is of importance in apoptosis-deficient disorders such as cancer and autoimmune diseases. Fas-mediated apoptosis involves translocation of Fas--and downstream signaling molecules--into lipid rafts, a process that can be pharmacologically modulated. FasL-independent clustering of Fas in membrane rafts generates high local concentrations of death receptor providing scaffolds for coupling adaptor and effector proteins involved in Fas-mediated apoptosis. Thus, lipid rafts act as the linchpin from which a potent death signal is launched, becoming a new promising anticancer target. These findings set a novel framework for the development of more targeted therapies leading to intracellular Fas activation and recruitment of downstream signaling molecules into Fas-enriched lipid rafts.