The cross-linking enzyme, Transglutaminase 2 (TGase 2), contributes to physiological homeostasis and plays a role in cell death and survival. We previously showed that down-regulation of TGase 2 by cystamine or synthetic peptide R2 promotes apoptosis in drug-resistant cancer cells by restoring the level of I-kBa, leading to inactivation of NF-kB. To better define the action of TGase 2, its expression was blocked by small interfering RNA. This interference rendered, the doxorubicin-resistant breast cancer cells, highly susceptible to doxorubicin-induced apoptosis. This susceptibility, was associated with decreased levels of the cell-survival factors BCl2 and BCLXL whereas the level of BAX remained un-changed. Together, the findings support the view that TGase 2 leads to drug-resistance by up-regulating the level of survival factors via NF-kB activation.