GREAT is a computational tool designed to improve the functional interpretation of cis-regulatory regions by integrating distal binding events and reducing false positives. It uses a binomial test to account for variability in gene regulatory domains and incorporates annotations from 20 ontologies. GREAT is available as a web application and can be applied to various functional genomic datasets, including ChIP-seq, open chromatin, and comparative genomics. The tool addresses the limitation of previous methods that only considered proximal binding events, which often missed over half of the observed binding events. GREAT uses a regulatory domain approach, defining regions that extend beyond the immediate promoter to include distal regions. This allows for a more accurate assessment of gene function by considering the broader regulatory landscape. GREAT was tested on multiple ChIP-seq datasets, including those for SRF and p300, revealing novel functions and testable hypotheses. For example, SRF was found to regulate genes associated with the actin cytoskeleton, a finding not detected by gene-based tools. Similarly, p300 binding in mouse limb tissue was shown to be functionally relevant to limb development, with GREAT identifying enriched terms related to limb-specific expression. The tool also demonstrated the importance of distal binding events in functional enrichment, as restricting regulatory domains to short distances reduced the number of enriched terms. GREAT's binomial test, which considers the entire genome, provided more accurate results than gene-based methods, especially in cases where regulatory domains were large. GREAT's ability to incorporate multiple ontologies and its robust statistical methods make it a valuable tool for interpreting genome-wide cis-regulatory data. It supports both human and mouse genomes and can be used to analyze a wide range of functional genomic datasets. The tool is available online and can be integrated with other bioinformatics applications. Overall, GREAT improves the accuracy and comprehensiveness of functional annotations for cis-regulatory regions, providing insights into the biological roles of these regions in gene regulation.GREAT is a computational tool designed to improve the functional interpretation of cis-regulatory regions by integrating distal binding events and reducing false positives. It uses a binomial test to account for variability in gene regulatory domains and incorporates annotations from 20 ontologies. GREAT is available as a web application and can be applied to various functional genomic datasets, including ChIP-seq, open chromatin, and comparative genomics. The tool addresses the limitation of previous methods that only considered proximal binding events, which often missed over half of the observed binding events. GREAT uses a regulatory domain approach, defining regions that extend beyond the immediate promoter to include distal regions. This allows for a more accurate assessment of gene function by considering the broader regulatory landscape. GREAT was tested on multiple ChIP-seq datasets, including those for SRF and p300, revealing novel functions and testable hypotheses. For example, SRF was found to regulate genes associated with the actin cytoskeleton, a finding not detected by gene-based tools. Similarly, p300 binding in mouse limb tissue was shown to be functionally relevant to limb development, with GREAT identifying enriched terms related to limb-specific expression. The tool also demonstrated the importance of distal binding events in functional enrichment, as restricting regulatory domains to short distances reduced the number of enriched terms. GREAT's binomial test, which considers the entire genome, provided more accurate results than gene-based methods, especially in cases where regulatory domains were large. GREAT's ability to incorporate multiple ontologies and its robust statistical methods make it a valuable tool for interpreting genome-wide cis-regulatory data. It supports both human and mouse genomes and can be used to analyze a wide range of functional genomic datasets. The tool is available online and can be integrated with other bioinformatics applications. Overall, GREAT improves the accuracy and comprehensiveness of functional annotations for cis-regulatory regions, providing insights into the biological roles of these regions in gene regulation.