The amount of known protein structures is continuously growing, exhibited in over 95,000 3D structures freely available via the PDB. Over the last decade, pharmaceutical research has sparked interest in computationally extracting information from this large data pool, resulting in a homology-driven knowledge transfer from annotated to new structures. Studying protein structures with respect to understanding and modulating their functional behavior means analyzing their centers of action. Therefore, the detection and description of potential binding sites on the protein surface is a major step towards protein classification and assessment. Subsequently, these representations can be incorporated to compare proteins, and to predict their druggability or function. Especially in the context of target identification and polypharmacology, automated tools for large-scale target comparisons are highly needed. In this article, developments for automated structure-based target assessment are reviewed and remaining challenges as well as future perspectives are discussed.