Most colorectal carcinomas (CRCs) exhibit constitutively active Wnt signaling. We have reported that (a) the histone deacetylase inhibitor (HDACi)(2) sodium butyrate (NaB) modulates the canonical Wnt transcriptional activity of CRC cells in vitro and (b) a linear relationship exists between the increase in Wnt transcriptional activity and the levels of apoptosis in ten CRC cell lines treated with NaB. Herein we report that structurally different HDACis modulate Wnt signaling in CRC cells and a mechanism involved in this action is an increase in beta-catenin that is dephosphorylated at Ser-37 and Thr-41 residues. The increase of active (Ser-37 and Thr-41 dephosphorylated) beta-catenin in CRC cells treated with HDACis is initiated at the ligand level and the inhibition of this increase suppresses Wnt signaling and lowers the levels of apoptosis. CRC cells that develop resistance to the apoptotic effects of HDACis exhibit lower levels of active beta-catenin compared to apoptosis-sensitive parental cells and this resistance is reversed by increasing the levels of active beta-catenin. Results from comparative studies between HDACi-resistant and HDACi-sensitive cells suggest that non-histone targets of HDACis mediate the effects on Wnt signaling and apoptosis.