Members of the CD44 family of transmembrane glycoproteins emerge as major signal transduction control units. CD44 isoforms participate in several signaling pathways ranging from growth factor-induced signaling to Wnt-regulated pathways. The role of the CD44 family members in tumor progression and metastasis is most likely linked to the function of the various isoforms as signaling hubs. Increasing evidence suggests that these proteins are not solely cancer stem cell (CSC) markers but are directly involved in tumor and metastasis initiation. It is foreseeable that a link between the expression of CD44 isoforms in CSCs and their function as signaling regulators will be drawn in a near future.