Fragment-based drug discovery (FBDD), while still a relatively new approach, has been so successful for identifying ligands for proteintargetsthatitisalreadywidelyregardedasrepresentinga sea-change in drug discovery techniques. The strategy involves identifying small (typically ,300Da), low-affinity ligands (‘fragments’) and combining or expanding these to produce larger, higher-affinity ligands. The major advantage of FBDD over more traditional high-throughput screening is that FBDD providesamorerapidandeffectivemeansofidentifyingligands for a protein target. Because there are fewer possible fragmentsized molecules than lead- or drug-sized molecules, FBDD samples chemical space far more efficiently than traditional approaches and therefore requires far fewer compounds to be testedtoidentifysuitablehitsasstartingpointsfordevelopment. Furthermore, fragment-based screeningtypicallyprovidesmore ‘developable’ compounds than traditional drug discovery approaches,whichoptimiseamedium-tohigh-affinityhit.Most importantly, fragment methods produce lead candidates with physicochemical properties (described by Lipinski’s ‘rule of five’) that are likely to result in orally bioavailable compounds. FBDD also has the capability of developing inhibitors of protein–protein interactions (PPIs), about which the pharmaceutical industry has had major reservations in the past as drug targets; that skepticism, however, is gradually being eroded as blockers of such interactions progress to the clinic. Indeed, the recent approval of vemurafenib, a B-Raf(V600E) inhibitordevelopedbyPlexxikonforlate-stagemelanoma,validates