Subcellular organelles such as mitochondria, endoplasmic reticulum and the Golgi complex are involved in the progression of cell death program. Recent evidence unveils that Fas ligand-mediated apoptosis induces scrambling of mitochondrial and secretory organelles via a global alteration of membrane traffic that is modulated by apical caspases. On the basis of the biochemical nature of lipid rafts, composed by sphingolipids, including gangliosides and sphingomyelin, cholesterol and signaling proteins, it has been suggested that they are part of this traffic and can participate in cell remodelling leading to cell death program execution. Although detected in various cell types, the role of lipid rafts in apoptosis has been mostly studied in T cells, where the physiological apoptotic program occurs through CD95/Fas. In this review, the possible contribution of lipid rafts to the cascade of events leading to T cell apoptosis after CD95/Fas ligation is summarized. We focused on the paradigmatic component of rafts GD3, which can proceed from the cell plasma membrane (and/or from trans Golgi network) to the mitochondria via a microtubule-dependent mechanism. This transport may be regulated by CLIPR-59, a new CLIP-170-related protein, involved in the regulation of microtubule dynamics. Particular attention has been given to mitochondrial raft-like microdomains, which may represent preferential sites where key reactions take place. Indeed, GD3, by interacting with mitochondrial raft-like microdomains, may trigger specific events involved in the apoptogenic program, including mitochondria hyperpolarization and depolarization, fission-associated changes, megapore formation and release of apoptogenic factors. These findings introduce an additional task for identifying new molecular target(s) of anti-cancer agents.