The use of X-ray crystallography to derive three-dimensional structures for structure-aided drug design (SADD) is a common activity in drug discovery today. In this process, the structures of inhibitors or other ligands of interest complexed with their macromolecular target are solved and the structural information is used iteratively to design new molecules. The ability to form cocrystal complexes between a target protein and a ligand is essential to this process and therefore is of considerable interest to anyone practicing in this field. In the course of obtaining the necessary ligand-protein crystals, even with crystallization conditions well established for a protein of interest, obtaining co-structures with inhibitors either through cocrystallization or soaking is too often not successful. There are numerous potential reasons for this lack of success and this article outlines a number of possible factors that may be involved and discusses considerations that should be taken into account when designing successful experiments to obtain iterative costructures.