Wnt signaling is implicated in the initiation of human colorectal cancer (CRC). While the relationship between Wnt activity and proliferation is well known, studies have also shown an association between high levels of Wnt activity and apoptosis. Through analyses of ten human CRC cell lines, we have found that inhibitors of histone deacetylases (HDACis), such as butyrate, promote apoptosis of CRC cells through hyper-induction of Wnt signalingû thus, hyper-activation of Wnt activity by HDACis may represent a novel preventive and therapeutic strategy against CRC. Our findings may explain why studies on the protective role of dietary fiber and its product butyrate against CRC have yielded inconsistent findings. We believe that the variability in the levels of induced Wnt activity and apoptosis in CRC cells observed in vitro reflects the in vivo existence of CRC subtypes with variable degrees of responsiveness to butyrate. Given that Wnt activity has been linked to intestinal stem cell renewal and the migratory potential of CRC stem cells, this essay discussed the potential of modulation of Wnt signaling by HDACis as a therapeutic approach against CRC stem cells. Finally, we considered possible gene therapy approaches that target Wnt-positive CRC stem cells.