Crystallographic fragment screening is a technique for initiating drug discovery in which protein crystals are soaked or grown with high concentrations of small molecule compounds (typically MW 110-250 Da) chosen to represent fragments of potential drugs. Specific binding of these compounds to the protein is subsequently visualized in electron density maps obtained from analysis of X-ray diffraction data collected from these crystals. Theoretical and practical experience indicate that a suitably diverse library of fragment compounds containing only a few hundred compounds may be sufficient to provide a comprehensive screen of the protein target. By soaking crystals in mixtures of 3-10 compounds a fragment screen may be completed within ∼100 diffraction data sets. This data collection requirement may be met given reproducible well-diffracting protein crystals and robotic sample handling equipment at a high flux X-ray source. The leading practical issue for most crystallography laboratories that wish to launch a fragment screening project is the design and/or procurement of an appropriate fragment library. Although several off-the-shelf fragment libraries are available from chemical suppliers, the numbers, sizes, and solubility of the compounds in relatively few of these libraries are well-match to the specific needs of the crystallographic screening experiment. Informed consideration of the properties of compounds in the screening library, possibly augmented by additional filtering of available compounds with appropriate search tools, is required to design a successful experiment. The analysis of results from crystallographic fragment screening involves highly repetitive application of routine image data processing and structure refinement calculations from many very similar crystals. Efficient handling of the data applies a high-throughput structure determination methodology that conveniently packages the structure solution calculations into a single process that provides the crystallographer-analyst with ready-to-view maps for evaluating crystals for bound compounds.