The Protein Structure Initiatives have provided an increasing resource of high quality crystal structures of therapeutic targets for drug design; this resource is expanding at an exponential rate. Most of this data is held electronically in the public domain and provides an opportunity for the biotechnology and pharmaceutical companies to exploit this information to generate candidate ligands that interfere with the function of the protein. The challenge for drug discovery is to industrialize the design process to identify a good selection of primary scaffold structures that offer excellent starting points for medicinal chemistry to provide good lead compounds. Computational methods offer an in silico approach to performing design in situ within the site. The huge benefit of de novo methods is that they can be used to assess in silico large numbers of potential structures for their fit to the site before any synthesis is embarked upon. De novo design offers an overwhelming advantage to companies seeking to gain a patent estate for the most promising compounds.