In todays drug discovery projects, the use of virtual screening tools, either ligand-based or structure-based techniques, is gaining momentum. Taken separately, these techniques obviously present some genuine advantages on some specific tasks, for example and for a given target, it is possible to explore the local variation of the chemical space in terms of structure activity relationship (SAR), or to sample the pharmaco-topological profile of potential hit molecules in a target structure driven manner (docking). Thus, while inherent limits are associated with each of these screening techniques that are not about to be easily solved, their combination in a hybrid protocol can help to balance these limitations and capitalize on their mutual strengths. Here we review some recent studies integrating ligand- and structure-based screening protocols, and show how this concept directly benefits the quality of the hit molecules.