Aberrant activation of the WNT/beta-catenin signaling pathway is frequently involved in a broad spectrum of human malignancies. Alternative to genetic deletions and point mutations, epigenetic inactivation of negative WNT regulators, through DNA methylation of promoter CpG islands and/or histone modification, leads to the activation or amplification of aberrant WNT/beta-catenin signaling. In this review, we summarized the contribution of epigenetic dysregulation of WNT/beta-catenin signaling to tumorigenesis and highlighted the importance of epigenetic identification of negative regulators of this pathway as putative tumor suppressors. The reversal of these silenced regulators may be developed as potential cancer therapeutics.