Fragment-based drug design (FBDD) is a structure-based approach of ligand designing used in drug discovery. It involves the identification of low molecular weight fragments as hit and then their binding mode is determined using X-ray crystallography and NMR spectroscopy. The binding information retrieved facilitates the optimization of fragments as hits which are later on converted into drug-like molecules. The identified fragments bind efficiently and form high-quality binding interactions. X-ray protein crystallography is considered as one of the most reliable and sensitive biophysical methods used for screening that reduce the chances to come up with false positive hits. It also provides insight into the structural details of the protein–fragment complex at the atomic level. Therefore, the fragment-based screening by using X-ray crystallography can be considered as an efficient method to identify the binding hotspots on proteins that can be further explored by chemists and biologists for the discovery of new drugs.