Since the first report of monolayer graphene in 2004, macromolecules that exhibit sheet-like topology including two-dimensional (2D) materials and related molecular networks have promised a wealth of intrigue in both fundamental science and technology. 2D gives rise to important interfacial behavior including molecular absorption, adhesion, cohesion, and bio-interfacing during materials’ synthesis, processing, and applications. This dissertation focuses on molecular mechanisms governing the interfacial behavior of 2D materials and related molecular analogs. Chapter 1 provides an overview of the interfacial molecular mechanisms used for 2D macromolecules. Chapter 2 looks into the detailed mechanisms and control of functional molecules’ absorption on graphene oxide (GO) nanosheets. Chapter 3 builds a tool to understand how surface organic monolayers manipulate the adhesion of graphene. Chapter 4 explores reversible cohesive mechanisms in 2D synthetic networks using macrocyclic analogs that stack into high aspect ratio, lyotropic nanotubes. This dissertation ends with a complex interface between GO and cell surfaces in Chapter 5 to discuss how GO nanosheets stimulate biological cells and find potential in cancer therapeutics. These results empower adhesive engineering, stacking control, and therapeutics design of 2D materials and related molecular networks.