The goal of this review is to briefly summarize the role of DKK proteins in the regulation of the canonical Wnt signaling pathway and to further focus on the intriguing complex functions of the most divergent member, DKK-3, which functions as both an oncogene and a tumor suppressor, and which has promise as either a prognostic biomarker or a therapeutic target in human cancers. This evidence concerns the gene DKK3 and neoplasm.