The goal of this paper is to review the variety of approaches adopted to improve lead generation, and make the process easier for the chemist, faster and more likely to succeed in later phases of drug development. Our analysis shows that successful lead generation requires not only an accurate definition of the needs (to define the most relevant assay protocols and readouts), but most of all a good hit as a starting point. It also appears that teams where techniques are combined are more successful in that difficult game.