Filamentous fungi are believed to be in a state of a perpetual “chemical arms race” with other soil inhabitants, as evidenced by their extremely diverse mycotoxin repertoire. Biosynthesis of mycotoxins and other small bioactive molecules called secondary metabolites is controlled by gene clusters, which seem to be the most variable segments of fungal genomes. The availability of completely sequenced genomes of Aspergillus fumigatus and closely related species allowed us to get insights into evolutionary mechanisms behind this chemical diversity. Comparative analysis of orthologous clusters revealed that they go through long evolutionary intervals of relative stability, presumably until corresponding bioactive products lose their adaptive value. These stable periods in cluster evolution are interrupted by short intervals of rapid change when new products may emerge. We have outlined five putative mechanisms that may ensure the quick evolutionary turnover of clusters including de-novo assembly, segmental duplication, translocation, accelerated differentiation, and differential loss of clusters in various Aspergillus lineages.