Due to structural genomics initiatives and a variety of technological advances, structural information about protein targets and their ligand complexes is currently being accumulated at an unprecedented pace. The continuously increasing amount of protein structures has considerable implications for structure-based drug design. On the one hand, it gradually improves the knowledge-base about proteins and molecular recognition, allowing to derive refined rules that might be used as scoring functions or in related tools for drug design; examples of such newly derived scoring functions will be given. On the other hand, however, it represents a significant challenge for current drug design techniques, which in most of the cases still operate on single protein structures in a single conformation, considering multiple protein structures and different conformations at best in a serial way, one after the other, but rarely in a parallel fashion. Such parallel consideration of multiple protein structures, however, would not only allow to simultaneously target different proteins, but also to address issues of ligand selectivity and aspects of protein flexibility in ligand binding. “In-situ cross-docking” will be presented as an approach to carry out such simultaneous docking to multiple target structures.