Investigation of isostructurality leads to a deeper understanding of close-packing principles and contributes to the ability of crystal engineering. A given packing motif may tolerate small molecular changes within a limit. Slight alterations of a crystal packing arrangement are carried out in order to fine-tune the structural and macroscopic properties, keeping the balance of the spatial requirements and electrostatic effects of the altered molecules in the crystals, preserving their isostructurality. Even so, the definition of isostructurality is not explicit about several issues. Are the corresponding structures required to have the same stoichiometry, Z', symmetry elements and the same space group? Because it is not obvious in the definition, studies on structure analysis and software calculating various numerical descriptors developed for the quantitative comparison of the degree of similarity of isostructural crystals self-define their criteria. The extent of the difference between corresponding crystal structures referred to as isostructural is not limited. Should it be determined numerically? There is nothing in the definition about a demand for similar supramolecular arrangements in isostructural crystals. Should the similarity of supramolecular interactions be a criterion of isostructurality? The definition of isostructurality deserves reconsideration regarding symmetry, measure of similarity and formation of supramolecular interactions.