In this issue of Blood , Ren et al investigate mechanisms underlying a novel strategy to block multiple myeloma (MM) cell proliferation by targeting the heparin sulfate (HS) proteoglycan syndecan-1 and identify the Wnt/β-catenin pathway as a critical mediator of this approach. If validated, these findings could lead to new therapeutic strategies in MM that may be particularly effective in circumventing microenvironmental forms of resistance in this disorder. 1