In nature, extraordinary material properties are typically achieved by combining constituents well differing in their microstructure and mechanical properties, which form very tough, hard and damage resistant architectures. The key for these outstanding properties is the variation in material microstructure and mechanical property distributions over large scales. In this work, various innovative design strategies for an enhancement of mechanical properties of nanostructured materials will be presented, which rely on compositional, microstructure and mechanical property depth-distributions and dedicated grain-boundary and interface design. One of the strategies to achieve specific physical properties of nanostructured materials is to tailor their composition and microstructure. Examples of a cross-sectional combinatorial approach for the development of films with dedicated microstructure and properties will be given for CrN and TiN-based graded systems exhibiting variations of hardness, stress state and fracture toughness across the thickness. Another approach in which microstructurally and mechanically different constitutents are combined in a specific architecture to enhance fracture resistance of the material by controlling the crack propagation will be demonstrated for multilayer films consisted of hard ceramic and elastic layers. The microstructure- and property-dependent mechanisms controlling crack propagation (e.g. deflection by weak interfaces or crack path tortuosity) with subsequent toughness enhancement will be discussed in detail. In addition, a special attention was paid to a new strategy for fracture toughness enhancement by grain-boundary engineering where crack propagation is inhibited by deflection of cracks at interfaces of columnar grains designed with chevron architecture. In this way, even common nanocrystalline brittle materials may exhibit considerably enhanced fracture toughness.