Fundamentally different strategies for transcriptional regulation are revealed by analysis of binding motifs

To regulate a particular gene, a transcription factor (TF) needs to bind a specific genome location. How is this genome address specified amid the presence of ~10^6^-10^9^ decoy sites? Our analysis of 319 known TF binding motifs clearly demonstrates that prokaryotes and eukaryotes use strikingly different strategies to target TFs to specific genome locations; eukaryotic TFs exhibit widespread nonfunctional binding and require clustering of sites in regulatory regions for specificity.