Metal organic frameworks (MOFs), also known as coordination polymers/networks, have experienced a rapid upsurge in the last 20 years in part due to the precise visualization of their atomic arrangement in the solid state. Structure–function relationship properties in MOFs is a key step to understand the potential of a material for its applications in advanced technologies, which can be only understood if full structure determination is carried out. Single crystal X-ray diffraction is the most reliable technique for the 3D description of the atomic arrangement of a crystalline material, but it needs a suitable single crystal both in size and in quality. Sadly, it often occurs that it is not possible to grow crystals of enough quality for single crystal XRD analysis. In MOF synthesis, rather often the products of certain synthetic approaches such as fast crystallization or mechanochemical reactions are obtained as powders. Also, gas, temperature, and solvent induced reactions render single crystals unsuitable for single crystal XRD. In such cases, structure elucidation of MOFs must be carried out using ab initio powder XRD analysis. Unfortunately, structure solution from powder XRD data is more complicated than that from single crystal XRD data. In this article, a short overview of crystal structure solution from powder XRD and how this technique has been applied in the structure solution of MOFs using direct-space strategy is given. Examples of microcrystalline MOFs obtained by solvothermal methods, synthesized by instant synthesis and mechanochemical methods and products obtained after solid-state reactivity are highlighted. The reported cases are challenging structure solution examples carried out by direct-space strategy using powder XRD data, and show that ab initio powder XRD structure solution is a powerful technique that allows many chemical reactions whose products cannot be carried out by single crystal X-ray analysis to be understood. Hopefully, the strength of ab initio powder XRD structure elucidation with the few cases shown in this Perspective will encourage members of this field of research to exploit this technique to make further progress in MOF chemistry.