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In addition, Fragment-Based approaches for drug discovery and even conventional SBDD protocols quite often encounter difficulties in introducing ligands either by soaking or co-crystallization of low affinity compounds. Often, this is because the active sites of the targets of interests are ocuppied by salts, additives or other chemicals that preclude the succesful crystallization/soaking of target:ligand complexes. We have explored the use of relative humidity control of protein crystals to overcome some of these issues. We have used crystals of PurE (EC.4.1.1.21), an enzyme from the purine biosynthesis pathway of B. anthracis as a test case. Our findings can be summarized as follows: i) using humidity control, it is possible to improve/optimize the diffraction quality of crystals soaked with ligands/inhibitors; ii) optimization of the relative humidity can compensate for the deterioration of the diffraction pattern that is observed upon desalting crystals grown in high salt; iii) combining de-salting protocols with PEG addition it is possible to achieve very high concentrations of weak ligands (5-10 mM range) in soaking solutions; and iv) fine control of the relative humidity of the crystals soaked in these solutions can compensate for the deterioration of crystal diffraction and restore 'high resolution' diffraction for SBDD and FBDD.