Transcription factors (TFs) and their combinatorial control on cis-regulatory elements play critical role in the co-expression of genes. This affects the interaction of genes in the transcriptome and thus may affect signals that cascade through cellular pathways. Using a combination of bioinformatic approaches, we sought to identify such common combinations of TFs in a set of ethanol-responsive (ER) genes and assess the role of ethanol in affecting multiple pathways through their co-regulation. Our results show that the metallothionein genes are regulated by TF motifs cAMP responsive element binding protein (CREB) and metal-activated transcription factor 1 and primarily involved in zinc ion homeostasis. We have also identified new target genes, Synaptojanin 1 and tryptophan hydroxylase 1, potentially regulated by this module. Altered arrangement of TF-binding sites in the module may direct the action of these and other target genes in intracellular signaling cascades, cell growth and/or maintenance. In addition to CREB, other key TFs identified are ecotropic viral integration site-1 and SP1. These modulate the contribution of the target ER genes in cell cycle regulation and apoptosis or programmed cell death. Multiple lines of evidence confirm the above findings and indicate that different groups of ER genes are involved in different biological processes and their co-regulation most likely results from different sets of regulatory modules. These findings associate the role of the ER genes studied and their potential TF modules with alcohol response pathways and phenotypes.