Over the last 20 years Fragment-based drug discovery has developed as an alternative approach for the generation of novel small molecule drug candidates. This approach for lead generation has distinct advantages over conventional bioassay-based screening in that low-affinity but highly ligand efficient fragments can be routinely identified using biophysical techniques such as X-ray crystallography, NMR and calorimetry. These “fragment hits” can then be rapidly optimized for potency and DMPK properties using iterative cycles of medicinal chemistry and structure-based drug design. Using this approach new drug candidates with good ligand efficiencies and optimal drug-like properties can be generated for a range of therapeutics targets, a selection of which will be described in this talk. Another major advantage of Fragment-based discovery resides in the ability to sample chemical space in a highly efficient manner. This has resulted in the discovery of novel allosteric pockets on key protein targets. In this talk I will also describe how fragments can probe the molecular complexity of a protein surface to identify such pockets, which may have a functional role.