Although the MUC13 transmembrane mucin is aberrantly overexpressed in colorectal cancer, the biological functions of MUC13 are unknown. Our previous studies have demonstrated that MUC13 is highly expressed by >90% of colorectal cancer (CRC), typically with aberrant cytoplasmic localisation.1 We have also shown that MUC13 is a potent inhibitor of apoptosis in normal intestinal epithelial cells and in human CRC cells,2 suggesting that MUC13 may be an important new therapeutic target in colorectal cancers. Our current aim was to identify the mechanisms by which MUC13 inhibits apoptosis and determine the importance of MUC13-dependent inhibition of apoptosis for resistance of human CRC cells to clinically used cytotoxic and biological drugs in vitro and in vivo. Using MUC13 siRNA silencing in LS513 and LIM2463 CRC cells, the present studies demonstrated that CRC cells in which MUC13 has been silenced were more susceptible to apoptosis induced by a broad range of apoptotic stimuli including: actinomycin-D, UV irradiation, TRAIL, and cytotoxic drugs (5-fluorouracil, vincristine, doxorubicin) used for cancer chemotherapy. We also demonstrated that MUC13 attenuated mitochondrial cytochrome c release. In concert with these results:1) MUC13 increases the expression of the anti-apoptotic BCL2L1 (BCLXL) protein (but not BCL2) and suppresses the expression of the pro-apoptotic BAX protein, 2) MUC13 associates with p53, and this interaction is increased by apoptotic stimuli, and 3) MUC13 cytoplasmic domain translocates to the nucleus in CRC cells consistent with a role in transcriptional regulation, possibly in concert with p53. These novel findings indicate that MUC13 is an important regulator of apoptosis in human CRC cells, and targeting the anti-apoptotic function of MUC13 could be an efficacious way to sensitise colorectal cancer cells to a broad range of therapies triggering apoptotic cell death.