The aim of this chapter is to shed light on the effects of grain boundary segregation on microstructural evolution in nanostructured metallic materials as well as on their mechanical properties. Several key topics will be covered. First, a brief explanation of mechanical stress-driven grain growth in nanostructured Al, Ni, and Cu thin films will be provided in terms of a deformation mechanism map. It will become clear that the excess energy of grain boundaries enable the nanostructured metals to suffer from significant microstructure evolution via dislocation-boundary interactions during plastic deformation even at room temperature. Manipulation of grain boundary structures/properties via dopants segregation at grain boundaries to inhibit grain coalescence associated with remarkably enhanced mechanical properties is then discussed in three representative binary Cu-based systems, i.e., Cu-Zr, Cu-Al, and Cu-W. This is finally followed by a summary of this chapter.