The structures of compounds with proven relevance to nature have fuelled numerous research and development programs aimed at the discovery of novel bioactive small molecules. Thus, natural products (NPs) created in evolution have been and continue to be a rich source of drugs, and they have inspired different principles for bioactive small molecule discovery including diversity-oriented synthesis, the complexity-to-diversity approach, and biologyoriented synthesis. In light of the limited coverage of biologically relevant chemical space explored in evolution, we have recently introduced the pseudo-natural product (pseudo-NP; PNP) concept. The PNP strategy combines evolutionary logic with synthetic chemistry to accelerate exploration of NP-like chemical space, and, to this end, pseudo-natural products combine fragments derived from NPs or fragment-sized NPs in ways that are not found in nature. They thereby escape the structural boundaries of current biosynthetic pathways and expand coverage of NP-like chemical space not populated by NPs, while pertaining their properties, in particular biological relevance. PNP collections were typically synthesized in 2-5 step reaction sequences which frequently include asymmetric complexity-generating transformations often forming multiple stereogenic centers. Investigation of pseudo-NP collections may lead to the discovery of novel chemotypes for unexpected targets or the identification of unprecedented bioactivities. For instance, we identified novel pseudo-NP inhibitors of glucose transporters , kinases , and the first inhibitors of the cholesterolshuttling protein GRAMD1A and the Rho-protein chaperone Rho-GDI. In order to unravel whether the synthesis and biological evaluation of PNPs might have been explored in a wider sense before, for instance driven by intuitive inclusion of NP structures in compound library design, we recently developed the natural product fragment combination (NPFC) tool. This tool allows the identification and classification of PNPs in large compound collections by identifying NP fragments and their combination types in chemical structures. Indeed, application of the NPFC tool to the ChEMBL database, v26 revealed that PNPs have been synthesized and investigated for bioactivity before widely, and that PNPs define a major fraction of bioactive compounds as described in the ChEMBL database.