Abstract: It was found that TRAIL-induced death signaling was largely diminished by lysosomal degradation system. Inhibition of lysosomal degradation by small molecules led to accumulation of DR5 in lysosomes and reversed TRAIL resistance in almost all cancer cells. Redirecting TRAIL-induced signaling away from lysosomal degradation may therefore induce massive cell death and overcome TRAIL resistance. Taking advantage of bioactive protein transduction domains (PTD) and signaling peptides, such as TAT peptide from HIV TAT protein, NLS (nuclear localization signal), MTS (mitochondrial targeting sequence), a series of new TRAILs fused with these peptides was constructed. It was found that TRAIL fused with bioactive peptide exerted remarkably high potency in inducing cell death in cancer cells, but not normal cells.