The results demonstrate that in human cholangiocarcinoma cells, (i) Hedgehog pathway inhibition sensitizes human cholangiocarcinoma cells to TRAIL-mediated apoptosis, in part, by down-regulating XIAP protein; (ii) XIAP repression by SMO inhibition occurs at the mRNA level as well, consistent with GLI-mediated enhancement of XIAP transcription; and (iii) inhibition of Hedgehog promotes TRAIL cytotoxicity independent of Bid, Bim, Bax, and Bak. Here, XIAP is linked to cholangiocarcinoma.