<jats:p> Recent fermentation studies have identified actinomycetes of the marine-dwelling genus <jats:italic>Salinispora</jats:italic> as prolific natural product producers. To further evaluate their biosynthetic potential, we sequenced the 5,183,331-bp <jats:italic>S. tropica</jats:italic> CNB-440 circular genome and analyzed all identifiable secondary natural product gene clusters. Our analysis shows that <jats:italic>S. tropica</jats:italic> dedicates a large percentage of its genome (≈9.9%) to natural product assembly, which is greater than previous <jats:italic>Streptomyces</jats:italic> genome sequences as well as other natural product-producing actinomycetes. The <jats:italic>S. tropica</jats:italic> genome features polyketide synthase systems of every known formally classified family, nonribosomal peptide synthetases, and several hybrid clusters. Although a few clusters appear to encode molecules previously identified in <jats:italic>Streptomyces</jats:italic> species, the majority of the 17 biosynthetic loci are novel. Specific chemical information about putative and observed natural product molecules is presented and discussed. In addition, our bioinformatic analysis not only was critical for the structure elucidation of the polyene macrolactam salinilactam A, but its structural analysis aided the genome assembly of the highly repetitive <jats:italic>slm</jats:italic> loci. This study firmly establishes the genus <jats:italic>Salinispora</jats:italic> as a rich source of drug-like molecules and importantly reveals the powerful interplay between genomic analysis and traditional natural product isolation studies.