Protein structure-based approaches in lead optimization and in silico screening of chemical libraries based on ligand docking have increasingly become part of many drug discovery projects, mainly due to the technical improvements in crystallography, the support of modern software, and the ever increasing computational power. The use of threedimensional structural information of therapeutic targets has long been recognized to initiate and accelerate many drug design programs in the past, since it offers the possibility of finding novel scaffolds, different from the existing active compounds. In spite of its many successes, structure-based virtual screening or high throughput docking still has several limitations at the methodological level, not the least of which is protein flexibility, ignored by most of the docking programs, which treat the receptor as a rigid entity. This may impact the accuracy of virtual screening at the docking and at the scoring level. The authors will first present the latest successful stories in high throughput docking. After reviewing the concepts of protein dynamics and binding, and its impact in ligand docking, the current approaches to incorporate protein mobility in docking-based virtual screening will be presented and discussed.