The establishment of metastasis requires that tumor cells acquire new adhesion and migration properties to emigrate from primary sites and colonize distant organs. CD44 is a cell membrane protein often overexpressed on tumor cells and, being both a cell-cell and cell-extracellular matrix adhesion protein, is well positioned to contribute to this process. Furthermore the interaction of CD44 with other cellular proteins involved in motogenesis and proteolysis is a determinant factor in cell migration and invasion. This review summarizes current knowledge on the role of CD44 in metastasis, as well as the challenges on understanding how this process operates.