We review the results of fragment-based high-throughput docking to the N-terminal bromodomain of BRD4 and the CREBBP bromodomain. In both docking campaigns the ALTA (anchor-based library tailoring) procedure was used to reduce the size of the initial library by selecting for flexible docking only the molecules that contain a fragment with favorable predicted binding energy. Ranking by a force field-based energy with solvation has resulted in small-molecule hits with low-micromolar affinity and favorable ligand efficiency. Importantly, the binding modes predicted by docking have been validated by X-ray crystallography. One of the hits for the CREBBP bromodomain has been optimized by medicinal chemistry into a series of potent and selective ligands.