The Ku heterodimer (Ku70/Ku80) plays a central role in DNA double strand break recognition and repair. It has been shown, more than ten years ago, that Ku is also expressed at the cell surface of different cells types along with its intracellular pool within the nucleus and the cytoplasm but involvement of Ku in cell-cell and cell-extracellular matrix adhesion has been only recently demonstrated. In addition, we have shown that Ku may have a second and unexpected activity in cell/microenvironment interaction. Indeed, Ku appears to be involved in extracellular proteolytic processes through its specific interaction, on the cell surface, with the matrix metalloprotease 9. Taken together, these results suggest that Ku function at the cell surface is likely to be important in tumour invasion. Various fundamental questions arise from these observations. How Ku is expressed on the cell surface, why a protein with completely unrelated functions also serve as an integrin-like molecule once expressed at the cell surface and is this functional moonlighting of Ku related to cell transformation remain open issues that will be discussed here.