>80% of a large number of tested siRNAs and shRNAs targeting CD95 or CD95 ligand (CD95L) induce a form of cell death that is characterized by the simultaneous activation of multiple death pathways and preferentially affects transformed and cancer stem cells. We now show that these si/shRNAs kill cancer cells through canonical RNAi by targeting the 3’UTR of critical survival genes in a unique form of off-target effect. We also provide evidence showing that the full length CD95L mRNA is also toxic and produces small Ago-associated RNAs. Overall design: Examination of small RNAs (18-23bp) pulled-down with Ago proteins in cells infected with either pLenti or pLenti- CD95L.