The first part of transcription factor binding site (TFBS) discovery, the input set, can be identified using either computational or experimental methods. Experimental techniques, such as chromatin immunoprecipitation (ChIP) (12) , have been successfully used to generate a genome scale mapping of approximate TF-binding positions (10, 13, 14) . Computational techniques, such as phylogenetic profiling (15, 16) and artificial neural networks, can also be used to identify sets of co-regulated genes. Both experimental and computational approaches, however, suffer from a significant false positive (FP) prediction rate. Inclusion of extraneous promoters in the input sets dilutes the enrichment of the shared TFBS sequences making computational TFBS discovery significantly more challenging (17) . We term such erroneously included promoters decoy sequences (DSs).