Crystal engineering is the design and synthesis of molecular solid-state structures with desired properties, based on the understanding and exploitation of intermolecular interactions. Layered zirconium phosphonates can be considered “tailor-made” materials that can be designed by exploiting the crystal engineering principles. They also represent a powerful class of materials for many applications in solid state chemistry, such as heterogeneous catalysis, nanocomposites chemistry, ion- exchange and separation and intercalation. The interest on these materials mainly resides on their high insolubility and on their chemical versatility. This class of compounds, widely developed from the beginning of the 70’s, is living a second youth in the recent years due to the use of novel and more sophisticated phosphonic ligands. However, their high insolubility also represents a drawback for their correct structural characterization and for the comprehension of the structure/reactivity relationship. Indeed, the possibility to get single crystals from these materials is extremely low and therefore only ab-initio XRPD structure determination methods can give suitable information on their structure. In this contribution a survey on the structure and reactivity of low dimensional zirconium phosphonates containing several functional groups (such as alkyl, arenes, carboxylates, amines, and heterocycles) is reported. A special attention will be devoted on the ab-initio XRPD structure determination methods working in the real space. The crucial role of the synthetic conditions and of non-covalent interactions as structural orientating factors will be discussed.