Late-stage cultures of filamentous fungi under nutrient starvation produce valuable secondary metabolites such as pharmaceuticals and pigments, as well as deleterious mycotoxins, all of which have remarkable structural diversity and wide-spectrum bioactivity. The fungal mechanisms regulating the synthesis of many of these compounds are not fully understood, but sirtuin A (SirA) is a key factor that initiates production of the secondary metabolites, sterigmatocystin and penicillin G, by Aspergillus nidulans. Sirtuin is a ubiquitous NAD⁺-dependent histone deacetylase that converts euchromatin to heterochromatin and silences gene expression. In this study, we have investigated the transcriptome of a sirA gene disruptant (SirAΔ), and found that SirA concomitantly repressed the expression of gene clusters for synthesizing secondary metabolites and activated that of others. Extracts of SirAΔ cultures grown on solid agar and analyzed by HPLC indicated that SirA represses the production of austinol, dehydroaustinol and sterigmatocystin. These results indicated that SirA is a transcriptional regulator of fungal secondary metabolism.