Cancer cells are progressively developing resistance to various inducers of cell death. We have focused on mortalin, the mitochondrial hsp70, an essential housekeeping protein. Mortalin was shown to protect cells from cell senescence, apoptosis and damage by oxygen radicals. We reported that mortalin confers on cancer cells resistance to complement-dependent cytotoxicity (CDC). CDC is activated by the complement C5b-9 complexes upon their assembly within the plasma membrane. Cells protect themselves by blocking C5b-9 assembly and by its elimination from their surface. We have shown that mortalin plays a role in C5b-9 elimination. Silencing of mortalin with specific siRNA reduced C5b-9 elimination and enhanced cell sensitivity to CDC. Similarly, the cationic rhodacyanine dye MKT-077, a mortalin inhibitor, enhanced CDC. Over-expression of mortalin led to enhanced cell resistance to C5b-9. Mortalin was shown to target the C8 and C9 complement components in C5b-9 through its ATPase domain and inhibits C5b-9 assembly and stability. We hypothesized that mimetic peptides of mortalin will block the protective functions of mortalin and will permit sensitization of cancer cells to cell death. Several mimetic peptides were designed based on predicted mortalin surface interaction sites and were synthesized with a cell penetration TAT-tag. Several of the peptides were shown to enhance CDC of cancer cells. Furthermore, mortalin mimetic peptides also induced cancer cell death as single agents. The mode of action of the toxic peptides is being investigated and in parallel, the peptides are being assessed as therapeutic agents for cancer.