Here we report (1) that ceramide synthase-6 (CERS6), an enzyme responsible for the generation of C16 ceramides, is overexpressed in T-cell ALL cells compared with T lymphocytes and PBMCs; (2) that genetic modification of CERS6 in T-cell ALL cell lines resulted in significant changes in sensitivity to chemotherapeutic drugs; and (3) that CERS6 binds to Fas and renders resistance to chemotherapy via the extrinsic apoptotic pathway by interfering with the Fas–FADD association in ALL cells. This evidence concerns the gene FAS and acute lymphoblastic leukemia.