Natural products (NPs) are the most historically bountiful source of chemical matter for
drug development—especially for anti-infectives. With insights gleaned from genome mining, interest
in natural product discovery has been reinvigorated. An essential stage in NP discovery is structural
elucidation, which sheds light not only on the chemical composition of a molecule but also its novelty,
properties, and derivatization potential. The history of structure elucidation is replete with techniquebased
revolutions: combustion analysis, crystallography, UV, IR, MS, and NMR have each provided
game-changing advances; the latest such advance is genomics. All natural products have a genetic basis,
and the ability to obtain and interpret genomic information for structure elucidation is increasingly available at low
cost to non-specialists. In this review, we describe the value of genomics as a structural elucidation technique, especially
from the perspective of the natural product chemist approaching an unknown metabolite. Herein we first introduce the databases
and programs of interest to the natural products chemist, with an emphasis on those currently most suited for general
usability. We describe strategies for linking observed natural product-linked phenotypes to their corresponding gene
clusters. We then discuss techniques for extracting structural information from genes, illustrated with numerous case examples.
We also provide an analysis of the biases and limitations of the field with recommendations for future development.
Our overview is not only aimed at biologically-oriented researchers already at ease with bioinformatic techniques,
but also, in particular, at natural product, organic, and/or medicinal chemists not previously familiar with genomic techniques.