Evolution is the fundamental process by which natural selection, genetic variation, and fitness adaptations can shape diversity in nature. At the foundation of natural ecosystems, small molecule chemical compounds, called specialized metabolites, play important ecological roles and mediate complex community interactions. Specialized metabolites are genetically encoded in biosynthetic gene clusters (BGCs) in the genomes of the producing organisms; thus, BGCs can undergo evolutionary diversification resulting in nature’s incredible chemical diversity. However, the process by which this diversification occurs is unknown. We can use phylogenetic methods to assess the diversity and distribution of specialized metabolite BGCs to better understand the dynamics of evolutionary chemical innovation. The goal of this dissertation was to develop new tools to identify novel targets of BGC biosynthetic potential and investigate the contrasting evolutionary history of different BGCs in the genus Salinispora to gain insight into the drivers of chemical diversity. First, I helped develop the updated NaPDoS2 webtool which identifies and characterizes polyketide and non-ribosomal peptide biosynthetic potential based on phylogenetically conserved domains in genomic, metagenomic, and targeted-amplicon sequencing data. Next, I used NaPDoS2 to assess the polyketide biosynthetic potential in 620,000 bacterial, archaeal, viral, plasmid, fungal, plant, agal, protist, and animal genomes across the tree of life. The second goal of this dissertation was to investigate the evolutionary patterns BGC diversity in the marine obligate actinomycete Salinispora. First, I uncovered an unexpected distribution and diversity of the Salinispora salinipostin (spt) BGC across all bacteria, including evidence that the entire spt BGC was exchanged from Salinispora arenicola to S. tropica in a location-dependent manner. Next, I applied a similar phylogenetic approach to the pacificamide (pac) BGC and found that the Salinispora pac had unique gene organization and limited distribution in three divergent Actinomycetia families. To expand my comparative analyses, I isolated and genome-sequenced 99 new “microscale” Salinispora strains—including three species of S. arenicola, S. oceanensis, and S. pacifica— from a 1m2 quadrant of marine sediment in Fiji. I found that there was significant genomic diversity within the microscale genomes, including S. arenicola sub-species diversification and unique BGCs. To investigate this further, I compared the lanthipeptide ribosomally synthesized and post-translationally modified (RiPP) BGC precursor peptide products, uncovering evidence of evolutionary radiation of diverse potential lanthipeptides. Finally, I explored possible mechanisms of BGC exchange in Salinispora by purifying and visualizing Salinispora plasmids. In conclusion, the results of this dissertation provide significant advancements in our ability to detect and classify biosynthetic potential across the tree of life. Additionally, the description of 99 new Salinispora genomes and the application of evolutionary phylogenetic methods to specialized metabolite BGC diversification on two different spatial scales contribute to our understanding of Salinispora genomic diversity and patterns of BGC-mediated chemical innovation.