Designing the molecular structure of single-crystals using directional well-defined non-covalent bonds has recently become a rapidly growing area of research. This approach has the potential to engineer molecular materials with sensing functions. We use these methods to develop interfacial crystal biosensors where small molecules or proteins are recognized at crystal lattices, and by using quartz-based balances generate fast-response biosensors. Single-crystal X-ray crystallography is used to characterize the molecular crystal structure. Although it is very difficult to engineer crystal packing patters (i.e. space group preference), our approach focuses more on engineering directional non-covalent networks that propagate hydrogen bonds and metal-ligand interactions with specific space-orientations along the crystallographic axes. We also explore the physical and chemical properties that arise from the crystal networks. For example, when paramagnetic transition metals are used, the non-covalent interactions often allow for the singlet electrons to couple ferromagnetically and generate molecular magnets at low temperatures.