Constitutive canonical Wnt signaling, resulting from mutations in the adenomatous polyposis coli (APC), beta-catenin, or axin genes, has been implicated in the initiation of most human colorectal cancers (CRCs). Some of the proposed approaches for CRC prevention and treatment involve the downregulation of canonical Wnt activity in an attempt to inhibit proliferation and promote apoptosis of the neoplastic cells. However, a number of studies have shown an association between high levels of canonical Wnt transcriptional activity and apoptosis. This relationship is also supported by the "just right hypothesis" for CRC formation where, in CRC patients, a selection for APC mutations occurs that results in a moderate level of canonical Wnt signaling and mutations leading to high levels of Wnt signaling are selected against, presumably due to apoptosis. In comparative studies of 10 human CRC cell lines, we found that inhibitors of histone deacetylases (HDACis), one of which is used clinically, promote apoptosis of CRC cells, at least partially by hyperinduction of canonical Wnt signaling. Based upon these findings, we propose a new paradigm for the activity of HDACis in the prevention and treatment of CRCs and other Wnt signaling-positive cancers. Herein, we review the evidence for the relationship between hyper-induced canonical Wnt activity and enhanced apoptosis in HDACi-treated CRC cells, discussing the implications of this relationship for cancer prevention and treatment, and pointing out the possible caveats of treating these tumors with HDACis.