Inefficiencies associated with the traditional methods applied to natural product discovery include the isolation of previously described metabolites and the analysis of biosynthetically redundant strains. Recent advances in DNA sequencing technologies and our understanding of the molecular genetics of natural product biosynthesis provide newfound opportunities to improve the process by which natural products are discovered from microbial sources. These opportunities include the use of genomic fingerprinting methods to rapidly compare the biosynthetic gene diversity among large numbers of strains. Phylogenetic analyses are also proving useful in this regard and can be used to predict compound novelty and the potential number of biosynthetic gene clusters maintained by individual strains. These methods are being developed using a model group of marine actinomycetes belonging to the genus Salinispora as well as other marine-derived taxa. Two Salinispora strains for which complete genome sequences are available have been used to establish a Terminal Restriction Fragment Length Polymorphism (T-RFLP) fingerprinting method targeting modular polyketide synthases. Phylogenetic analyses have been used to identify strains that are biosynthetically rich and to accurately predict the production of specific compounds prior to chemical study. These approaches provide a culture-independent, genome-level assessment of biosynthetic potential that can be applied prior to fermentation and chemical analysis. Sequence based approaches such as these have tremendous potential to improve the process of small molecule discovery and increase the chemical diversity available for industrial applications.