Aberrant activation of the Wnt signaling pathway is a major trait of many human cancers. Due to its vast implications in tumorigenesis and progression, the Wnt pathway has attracted considerable attention at several molecular levels, also with respect to developing novel cancer therapeutics. Indeed, research in Wnt biology has recently provided numerous clues, and evidence is accumulating that the secreted Wnt antagonist Dickkopf-related protein 3 (Dkk-3) and its regulators may constitute interesting therapeutic targets in the most important human cancers. Based on the currently available literature, we here review the knowledge on the biological role of Dkk-3 as an antagonist of the Wnt signaling pathway, the involvement of Dkk-3 in several stages of tumor development, the genetic and epigenetic mechanisms disrupting DKK3 gene function in cancerous cells, and the potential clinical value of Dkk-3 expression/DKK3 promoter methylation as a biomarker and molecular target in cancer diseases. In conclusion, Dkk-3 rapidly emerges as a key player in human cancer with auspicious tumor suppressive capacities, most of all affecting apoptosis and proliferation. Its gene expression is frequently downregulated by promoter methylation in almost any solid and hematological tumor entity. Clinically, evidence is accumulating of Dkk-3 being both a potential tumor biomarker and effective anti-cancer agent. Although further research is needed, re-establishing Dkk-3 expression in cancer cells holds promise as novel targeted molecular tumor therapy.