The efficient exploration of biologically relevant chemical space is essential for bioactive compound discovery. Pseudo-natural products (PNPs), generated by the de novo combination of natural product fragments through complexity- and stereogenic character-generating transformations, enable exploration of novel chemical space for biological discovery. In nature, biological targets possessing intrinsic chirality preferentially select complementary active interactors, thereby driving the biological evolution of structures. Similarly, the PNP approach embodies a chemical evolution of structures, wherein combinatorial diversity and chirality serve as essential factors. I will illustrate the concept of the PNP approach through two drug discovery endeavours. First, we report the synthesis of pyrrolo[3,2-c]quinolines—embodying the rarely combined pyrrolidine and tetrahydroquinoline fragments—via a highly enantioselective intramolecular exo-1,3-dipolar cycloaddition catalysed by the AgOAc/(S)-DMBiphep complex (up to 98% yield, up to 99% ee). Biological evaluation of the PNP collection identified a structurally novel and potent Hedgehog signalling inhibitor targeting Smoothened. Complementarily, a diverse PNP strategy merging biological relevance with diversity-oriented synthesis was applied: from a common divergent intermediate, indole dearomatization methodologies afforded three-dimensional frameworks that were further diversified via intramolecular coupling and/or carbon monoxide insertion, yielding 154 PNPs across eight structurally distinct classes. Cheminformatic analyses confirmed structural diversity between classes, and biological investigations revealed four inhibitors of Hedgehog signalling, DNA synthesis, de novo pyrimidine biosynthesis and tubulin polymerization, derived from four different PNP classes.