The availability of complete genome sequences and global gene expression profiling represents a promising strategy for reverse engineering genetic regulatory circuits. We are describing a novel strategy for analyzing gene expression and genomic sequence to elucidate the cis-regulatory design in terms of higher order modular architecture of the transcription control regions. The large-scale transcriptional activity was assessed in two distinct experimental models represented by reovirus infection and brain extracts from mice selectively bred for high vs. low alcohol functional tolerance. A comparison of the 2000 nucleotides of the upstream sequences of the most differentially expressed genes revealed regions of significant similarity which displayed a highly conserved modular organization. Higher-order patterns of individual modules were also over-represented in the 5' upstream regions of the analyzed genes. The supermodules contain binding sites for multiple transcription factors and they tend to define the role of genes in processes involved in either viral infection or mechanisms responsible for different levels of alcohol functional tolerance. The supermodular design unravels a different aspect of the circuitry encoding cis-regulatory logic responsible for transducing the upstream signaling to control the expression of genes in similar biological processes.