Dickkopf-1 (DKK-1) is a well-established inhibitor of canonical Wnt-signaling that critically participates in the regulation of bone formation and has been implicated in the development and progression of bone metastases. While the skeleton was originally considered the sole site of DKK-1 synthesis, it has now become clear that the molecule is also highly expressed in T-cells, platelets and multiple cancer cells. In the past years, several new functions of DKK-1 in angiogenesis, cancer cell biology, immune homeostasis and inflammation have been revealed. These novel insights have paved the way for clinical trials investigating the efficacy of anti-DKK-1 antibodies in a variety of different malignancies, most of which are currently still ongoing. In this review, we discuss the evolution and recent advances in DKK-1 research and highlight clinical implications of the available knowledge on the molecule, especially in cancer. Finally, we emphasize outstanding questions and provide an outlook on potential future studies that will aid in further improving our understanding of the pleiotropic roles of DKK-1 in health and disease.