Secreted Frizzled Related Proteins (Sfrps) are a family of secreted proteins that can bind both to Wnt ligands and Frizzled receptors, thereby modulating the Wnt signalling cascades. Recent studies have shown that Sfrps can also interact with Wnt unrelated molecules such as RANKL, a member of the tumor necrosis factor family, Tolloid metalloproteinases or integrin-fibronectin complexes. Alterations in the levels of Sfrp expression have been recently associated with different pathological conditions, including tumor formation and bone and myocardial disorders. Here, we summarise the evidence that relates Sfrps with these diseases and discuss how the proposed multiple Sfrp interactions with Wnt related and unrelated pathways may explain their implication in such diverse pathologies.