Inverse design and inverse thinking are critical steps in the new materials developments (materials genome approach). When we design materials with specific functional properties, we often start with independent building blocks which possess well-defined molecular functions and precise chemical structures. Using the “Molecular Lego” approach, we can then, in some cases with multiple steps, assemble such elemental building blocks together in preferred secondary structures (or packing schemes) to construct materials possessing topologically mandated hierarchical structures with desired functions. In this talk, a unique approach along this inverse design and inverse thinking path will be presented. Various “giant molecules” based on “nano-atoms” are designed and synthesized. “Nano-atoms” refer to shape-persistent molecular nanoparticles (MNPs) such as fullerenes, polyhedral oligomeric silsesquioxanes, polyoxometalates, and folded globular proteins, and others. These “nano-atoms” possess precisely-defined chemical structures, surface functionalities and molecular shapes, which serve as elemental units for the precision synthesis of “giant molecules” via methods such as click chemistry and other efficient chemical transformations. These “giant molecules” include, but are not limited to, giant surfactants, giant shape amphiphiles, and giant polyhedra. These “giant molecules” can assemble into diverse highly ordered building blocks (spherical and non-spherical) to further construct the thermodynamically stable and metastable hierarchical structures in the bulk, thin-film, and solution. Unconventional nanostructures can be obtained in various environments to exhibit specifically desired properties. This approach has provided a versatile platform for engineering nanostructures that are not only scientifically intriguing, but also technologically relevant.