The history of drug‐related protein crystallography and drug design is reviewed to show that “Lead Generation” is high‐lighted in the pharmaceutical industry nowadays. A new drug design method has been developed. The method gave very high success rate; 10–60 &percent; gave < 100 &mgr;M, 90 &percent; gave < 10 mM. The crystal structures of drug‐protein complexes have become even more important to give solid experimental bases for e.g. 1,000 designed structures and to find the new mechanisms of drug action. © 2004 American Institute of Physics