Pharmacophoresthree-dimensional (3D) arrangements of essential features enabling a molecule to exert a particular biological effectconstitute a very useful tool in drug design both in hit discovery and hit-to-lead optimization process. Two basic approaches for pharmacophoric model generation can be used by chemists, depending on the availability or not of the target 3D structure. In view of the rapidly growing number of protein structures that are now available, receptor-based pharmacophore generation methods are becoming more and more used. Since most of them require the knowledge of the 3D structure of the ligand-target complex, they cannot be applied when no compounds targeting the binding site of interest are known. Here, a GRID-based procedure for the generation of receptor-based pharmacophores starting from the knowledge of the sole protein structure is described and successfully applied to address three different tasks in the field of medicinal chemistry.