One hallmark of cancer is intrinsic or acquired resistance to apoptosis. Surprisingly, recent studies demonstrate that CD95/Fas/Apo1 and p53 upregulated mediator of apoptosis/PUMA (potent inducers of the death receptor and the mitochondrial apoptotic pathways, respectively) promote tumorigenesis. These findings provide important insights into the multifaceted roles of apoptosis in tumorigenesis.