Annexin II belongs to a family of calcium-dependent, phospholipid binding proteins. Annexin II was first identified as an intracellular protein and attributed intracellular functions. Although it lacks a signal peptide and its mechanism of secretion is unknown, extracellular annexin II has recently been found in several tissues as both soluble and membrane-bound protein. Cell-surface annexin II has been identified as a receptor for a number of polypeptide ligands. Extracellular annexin II may be important in several biological processes, such as fibrinolysis, cell adhesion, ligand-mediated cell signaling and virus infection. These processes provide several possibilities for therapeutic approaches targeting extracellular annexin II, and future research should further illuminate the biology of this molecule.