Resolved three-dimensional protein structures are a major source of information for understanding protein functional properties. The current explosive growth of publicly available protein structures is producing large volumes of data for computational modelling and drug design methods. Target-based in silico drug design tools aid design and optimize compounds to bind to specific targets. MED-SuMo is a powerful technology for comparing local regions on protein surfaces, allowing similarities to be discovered and explored. This is a target-based tool that can exploit all available macromolecule structures. Its computational efficiency differentiates its approach from widely used methods such as docking and scoring, or map-based methods. As a result, MED-SuMo contributes to a large variety of real-world drug discovery applications. We review specific applications where MED-SuMo performed a significant role. These examples include functional annotation, pocket profiling, structural superposition, and functional binding site classification. We also review cases where MED-SuMo provided an innovative solution to frequent undertakings of the medicinal chemist and molecular modeller during lead discovery and lead optimization. These further cases include drug repurposing and fragment-based drug design.