Syndecan-3 is a transmembrane proteoglycan, the largest of the four syndecan family members and the most mysterious. To date, the number of published studies involving syndecan-3 is only a small fraction of the number of studies involving the other subfamily member syndecan-1, yet, these few studies on syndecan-3 cover a whole range of biological functions and phenotypes suggesting that syndecan-3 might be the most eclectic and intereting of the four syndecans. In this review, we focus on what is currently known about the role of syndecan-3 in the musculoskeletal system, from development to aging, including regeneration and disease. We also briefly refer to known syndecan-3 functions in other tissues and systems in an attempt to summarize the most up-to-date knowledge while also instilling curiosity about this extraordinary biomolecule and, hopefully, inspiring more research into its biochemistry and biological functions.