One of the many obstacles in the development of new drugs lies in the limited number of therapeutic targets and in the quality of screening collections of compounds. In this review, we present general strategies for building target-focused chemical libraries with a particular emphasis on protein-protein interactions (PPIs). We describe the chemical spaces spanned by nine commercially available PPI-focused libraries and compare them to our 2P2I3D academic library, dedicated to orthosteric PPI modulators. We show that although PPI-focused libraries have been designed using different strategies, they share common subspaces. PPI inhibitors are larger and more hydrophobic than standard drugs; however, an effort has been made to improve the drug-likeness of focused chemical libraries dedicated to this challenging class of targets.