Scanning probe microscopy (SPM) is a powerful tool to study the structure and dynamics of molecules at surfaces and interfaces as well as to precisely manipulate atoms and molecules by applying an external force, by inelastic electron tunneling, or by means of an electric field. The rapid development of these SPM manipulation modes made it possible to achieve fine‐control over fundamental processes in the physics of interfaces as well as chemical reactivity, such as adsorption, diffusion, bond formation, and bond dissociation with precision at the single atom/molecule level. Their controlled use for the fabrication of atomic‐scale structures and synthesis of new, perhaps uncommon, molecules with programmed properties are reviewed. Opportunities and challenges towards the development of complex chemical systems are discussed, by analyzing potential future impacts in nanoscience and nanotechnology.