Recent studies have implicated genetic and epigenetic aberrations resulting in aberrant activation of the Wingless-Int (Wnt) pathway and thus influencing the initiation and progression of multiple myeloma (MM). Of major importance, these findings may lead to novel treatment strategies exploiting targeted modulation of Wnt signaling. This review describes the current status of knowledge concerning the role of Wnt pathway alteration in MM and outlines future lines of research and their clinical perspectives.