Background: The filamentous fungus Aspergillus niger is an exceptionally efficient producer of organic acids, which is one of the reasons for its relevance to industrial processes and commercial importance. While it is known that the mechanisms regulating this production are tied to the levels of ambient pH, the reasons and mechanisms for this are poorly understood. Methods: To cast light on the connection between extracellular pH and acid production, we integrate results from two genome-based strategies: A novel method of genome-scale modeling of the response, and transcriptome analysis across three levels of pH. Results: With genome scale modeling with an optimization for extracellular proton-production, it was possible to reproduce the preferred pH levels for citrate and oxalate. Transcriptome analysis and clustering expanded upon these results and allowed the identification of 162 clusters with distinct transcription patterns across the different pH-levels examined. New and previously described pH-dependent cis-acting promoter elements were identified. Combining transcriptome data with genomic coordinates identified four pH-regulated secondary metabolite gene clusters. Integration of regulatory profiles with functional genomics led to the identification of candidate genes for all steps of the pal/pacC pH signalling pathway. Conclusions: The combination of genome-scale modeling with comparative genomics and transcriptome analysis has provided systems-wide insights into the evolution of highly efficient acidification as well as production process applicable knowledge on the transcriptional regulation of pH response in the industrially important A. niger. It has also made clear that filamentous fungi have evolved to employ several offensive strategies for out-competing rival organisms.