Upregulation of metabolic and detoxification enzymes by the nuclear aryl hydrocarbon receptor (AhR)/aryl hydrocarbon receptor nuclear translocator (Arnt) complex is dependent upon transcriptional activation through binding to upstream enhancers, termed dioxin response elements (DRE). This mechanism, however, does not reasonably explain the tissue-, sex- and species-specific toxicity of AhR agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. Therefore, other potentially DRE-regulating genes were searched for in the Eukaryotic Promoter Database by searching for the core DRE sequence (5'-GCGTG-3'). An IUPAC search strategy revealed the existence of 1831 DREs in the 5' flanking region of 353 vertebrate, 104 invertebrate and 132 viral genes. Due to the functional importance of nucleotides flanking the core DRE sequence, we attempted to estimate the functionality of the extended DRE sequence string (5'-N₇GCGTGN₇-3') using MatInspector software. Each DRE sequence string was scored according to its relative similarity to a precompiled position weighted nucleotide distribution matrix derived from 25 selected AhR:Arnt binding sequences. Matrix similarity scoring of 10 bona fide DREs produced a cutoff score of 0.701, suggesting similarity scores above this value may be biologically functional. Matrix analysis of 1831 DREs resulted in 939 DREs in 423 promoters having scores above the cutoff value, which represent genes whose DREs have potential functionality. Subsequent ranking of DRE frequency and matrix similarity score prioritize these genes for subsequent experimental verification of DRE functionality. Due to the conserved nature of DRE binding, our results also suggest a role of the AhR:Arnt complex in viral gene regulation and the existence of ancestral AhR and Arnt orthologues in invertebrates, a hypothesis recently verified.