The acquisition of a cell polarity is a crucial requirement for a number of cellular functions, including apoptosis. Cell polarization is an actin cytoskeleton-driven process, through a connection between actin and an increasing number of membrane proteins. The major actors in this connection are ezrin, radixin and moesin, a family of proteins with a high level of homology. Their structure includes an epitope that links to membrane proteins and the other that binds to the actin molecule. In this review we discuss recent data showing that the Fas linkage to the actin cytoskeleton is ezrin mediated and it is an essential requirement for susceptibility to the Fas-mediated apoptosis. The ezrin region responsible of Fas binding consists of 18 aminoacids mapped on the median lobe of the ezrin FERM domain. This binding is specific and of key importance in the control of cell homeostasis. Moreover, Fas-ezrin co-localization, ezrin phosphorylation and early acquisition of susceptibility to Fas-mediated apoptosis, may have a role in some human diseases in which programmed cell death seems to be a central pathogenetic mechanism, such as AIDS.