The paper introduces GREAT (Genomic Regions Enrichment of Annotations Tool), a tool designed to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across the entire genome. Unlike previous methods that only consider binding events near genes, GREAT incorporates distal binding sites and controls for false positives using a binomial test over input genomic regions. GREAT integrates annotations from 20 ontologies and is available as a web application. The authors demonstrate the utility of GREAT by applying it to ChIP-seq data sets of multiple transcription-associated factors, including SRF, NRSF, GABP, Stat3, and p300, in different developmental contexts. They recover many functions of these factors that are missed by existing gene-based tools and generate testable hypotheses. GREAT is not limited to ChIP-seq data but can also be applied to open chromatin, localized epigenomic markers, and comparative genomics sets. The tool explicitly models the vertebrate cis-regulatory landscape through long-range regulatory domains and a genomic region-based enrichment test, allowing for the analysis of binding events far beyond proximal promoters. GREAT produces specific, accurate enrichments that provide insights into the biological roles of cis-regulatory data sets.The paper introduces GREAT (Genomic Regions Enrichment of Annotations Tool), a tool designed to analyze the functional significance of cis-regulatory regions identified by localized measurements of DNA binding events across the entire genome. Unlike previous methods that only consider binding events near genes, GREAT incorporates distal binding sites and controls for false positives using a binomial test over input genomic regions. GREAT integrates annotations from 20 ontologies and is available as a web application. The authors demonstrate the utility of GREAT by applying it to ChIP-seq data sets of multiple transcription-associated factors, including SRF, NRSF, GABP, Stat3, and p300, in different developmental contexts. They recover many functions of these factors that are missed by existing gene-based tools and generate testable hypotheses. GREAT is not limited to ChIP-seq data but can also be applied to open chromatin, localized epigenomic markers, and comparative genomics sets. The tool explicitly models the vertebrate cis-regulatory landscape through long-range regulatory domains and a genomic region-based enrichment test, allowing for the analysis of binding events far beyond proximal promoters. GREAT produces specific, accurate enrichments that provide insights into the biological roles of cis-regulatory data sets.