Fragment-based lead discovery is gaining momentum in both large pharmaceutical companies and biotechnology laboratories as a complementary approach to traditional screening. This is because fragment-based approaches require significantly fewer compounds to be screened and synthesized, and are showing a high success rate in generating chemical series with lead-like properties. Compared with traditional screening hits, the starting fragments have considerably lower molecular mass, and although the binding interactions of these fragments with a target protein are weak, they are structurally understood through X-ray crystallography or NMR, and they exhibit high 'ligand efficiency'. Here, we use examples from 25 different protein targets to describe chemical strategies that exploit this structural knowledge to rapidly develop fragments into high-affinity leads.