This chapter outlines the principles for selecting privileged scaffolds based on natural products (NPs) for the synthesis of focused compound libraries. It discusses the direction of the field as a whole and which areas are the most likely to see advancements in the coming years. The chapter outlines recent successful examples of applying biology-oriented synthesis (BIOS) to synthesize NP-inspired compound collections. It purposes of the approach is to reduce the synthetic complexity of NPs while retaining or even expanding their biological activity. To circumvent the aforementioned problems, several strategies to access NP-inspired compound collections have been established, including diversity-oriented synthesis (DOS) and BIOS. BIOS aims to synthesize small-molecule libraries based on NP scaffolds or cores. Using the guiding principles of structural classification of natural products (SCONP) and protein structure similarity clustering (PSSC) to select synthetic targets enables one to tackle biologically relevant areas of chemical space.