The Epithelial Cell Adhesion Molecule (EpCAM) is overexpressed in many cancers and EpCAM overexpression correlates with decreased survival. We show here that targeted methylation of the EpCAM promoter using an engineered zinc finger protein fused to a DNA methyltransferase leads to gene silencing and a reduction in cell proliferation. Our data indicate that targeted methylation of the EpCAM promoter could be an approach in the therapy of EpCAM overexpressing cancers.