Programmed molecular assemblies with molecular-level precision have always intrigued mankind in the quest to master the art of molecular engineering. In this regard, our review seeks to highlight the state of the art in supramolecular engineering. Herein we describe two-dimensional (2D) nanoarchitectonics of organic and organic–inorganic based hybrid materials. Molecular systems ranging from simpler hydrogen bonding driven bis-acylurea and cyclic dipeptide derivatives to complex peptoids, arylenes, cucurbiturils, biphenyls, organosilicons and organometallics, which involve a delicate interplay of multiple noncovalent interactions are discussed. These specifically chosen examples illustrate the molecular design principles and synthetic protocols to realize 2D nanosheets. The description also emphasizes the wide variety of functional properties and technological implications of these 2D nanomaterials besides an outlook for future progress.