Encoded within many microbial genomes, biosynthetic gene clusters (BGCs) underlie the synthesis of various secondary metabolites that often mediate ecologically important functions. Several studies and bioinformatics methods developed over the past decade have advanced our understanding of both microbial pangenomes and BGC evolution. In this minireview, we first highlight challenges in broad evolutionary analysis of BGCs, including delineation of BGC boundaries and clustering of BGCs across genomes. We further summarize key findings from microbial comparative genomics studies on BGC conservation across taxa and habitats and discuss the potential fitness effects of BGCs in different settings. Afterward, recent research showing the importance of genomic context on the production of secondary metabolites and the evolution of BGCs is highlighted. These studies draw parallels to recent, broader, investigations on gene-to-gene associations within microbial pangenomes. Finally, we describe mechanisms by which microbial pangenomes and BGCs evolve, ranging from the acquisition or origination of entire BGCs to micro-evolutionary trends of individual biosynthetic genes. An outlook on how expansions in the biosynthetic capabilities of some taxa might support theories that open pangenomes are the result of adaptive evolution is also discussed. We conclude with remarks about how future work leveraging longitudinal metagenomics across diverse ecosystems is likely to significantly improve our understanding on the evolution of microbial genomes and BGCs.