The effects of epigenetic modulation on secondary metabolite biosynthesis were investigated with five Aspergillus species cultured in the presence of either the DNA methyltransferase inhibitor 5-azacitidine or the histone deacetylase inhibitor vorinostat. With Aspergillus calidoustus and Aspergillus westerdijkiae, fermentation in the presence of vorinostat (100 μM) induced significant changes in secondary metabolite profile with examples of both induction and repression. We identified putative biosynthetic gene clusters for emericellamide in A. calidoustus and ochratoxin in A. westerdijkiae. A substantial induction in production levels was observed for two secondary metabolites: the diketopiperazine alkaloid phenylahistin in A. calidoustus and the polyketide penicillic acid in A. westerdijkiae, indicating the potential of epigenetic regulation for the activation of silent fungal biosynthetic pathways.