Covering: up to 2021Natural products research is in the midst of a renaissance ushered in by a modern understanding of microbiology and the technological explosions of genomics and metabolomics. As the exploration of uncharted chemical space expands into high-throughput discovery campaigns, it has become increasingly clear how design elements influence success: (bio)geography, habitat, community dynamics, culturing/induction methods, screening methods, dereplication, and more. We explore critical considerations and assumptions in natural products discovery. We revisit previous estimates of chemical rediscovery and discuss their relatedness to study design and producer taxonomy. Through frequency analyses of biosynthetic gene clusters in publicly available genomic data, we highlight phylogenetic biases that influence rediscovery rates. Through selected examples of how study design at each level determines discovery outcomes, we discuss the challenges and opportunities for the future of high-throughput natural product discovery.