Natural products (NPs) have played a pivotal role in medicine, providing treatments that have saved or enhanced an incalculable number of lives. Traditionally, NPs were discovered using microbial extracts in conjunction with the bioactivity/phenotype-driven “grind and find” methodology. While initially fruitful during the “golden age” of NP discovery, it was quickly realized this method is fraught with drawbacks; namely, rediscovery of known/widely distributed secondary metabolites. Bioinformatics-guided discovery of novel NPs is a promising approach to obviate these drawbacks. Ribosomally synthesized and post-translationally modified peptide (RiPP) NPs are uniquely suited for a bioinformatics-driven strategy since RiPPs are biosynthesized from a ribosomally-encoded precursor peptide that is collocated with tailoring enzymes in biosynthetic gene clusters. This chapter details how the bioinformatics tool Rapid ORF Description and Evaluation Online (RODEO) can be united with genomic enzymology workflows to rapidly expand knowledge of RiPP NPs and details several case studies of how RODEO was used to explore a known class of RiPP, identify the origins of a novel post-translational modification, and discover the founding members of a new class of RiPP. While RODEO and the methods detailed herein are focused on RiPP NPs, they are largely translatable to other NP classes, and we anticipate these methods can be broadly useful to researchers in NP discovery.