The ENCODE Project Consortium has expanded the Encyclopedia of DNA Elements (ENCODE) to provide a comprehensive resource for understanding the human and mouse genomes. This phase III of the ENCODE Project has generated 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE and Roadmap Epigenomics data. The project has developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements (cCREs), covering 7.9% and 3.4% of their respective genomes. A web-based server (SCREEN; http://screen.encodeproject.org) provides flexible, user-defined access to this resource. The human genome contains DNA-encoded instructions that are read, interpreted, and executed by the cellular protein and RNA machinery to enable the diverse functions of living cells and tissues. The ENCODE Project aims to delineate precisely and comprehensively the segments of the human and mouse genomes that encode functional elements. Functional elements are defined as discrete, linearly ordered sequence features that specify molecular products or biochemical activities with mechanistic roles in gene or genome regulation. The ENCODE Project has applied a succession of state-of-the-art assays to identify likely functional elements with increasing precision across an expanding range of cellular and biological contexts. The project has incorporated new assays such as RNA-binding-protein localization and chromatin looping, increased the depths at which current assays interrogate reference cell lines, and collected data over a greatly expanded biological range, with an emphasis on primary cells and tissues. The project has also incorporated and uniformly processed the substantial data from the Roadmap Epigenomics Project that conform to ENCODE standards. The ENCODE Project has generated nearly 6,000 new experiments in phase III that have extended previous phases of ENCODE in order to define and annotate diverse classes of functional elements in the human and mouse genomes. The project has systematically integrated DNA accessibility and chromatin modification data to create a categorized registry of cCREs in both the human and mouse genomes. The project has also developed a new web-based interface called SCREEN to facilitate access to the human and mouse registries and to facilitate their application to diverse biological problems. The ENCODE Project has expanded the range of experimental data to provide new insights into genome organization and function, and catalysed new capabilities for deriving biological understandings and principles. The project has defined core gene sets that correspond to major cell types using extensive new maps of RNA transcripts in a broad range of primary cell types. The project has described an expansive new genomic compartment of DNA elements that encode recognition sites for RNA-binding proteins, providing new insights into post-transcriptional regulation. The project has deeply mapped the co-occupancy patterns of human transcription factors in reference cell types and connected these with key biological features of promoters and distal enhancers. TheThe ENCODE Project Consortium has expanded the Encyclopedia of DNA Elements (ENCODE) to provide a comprehensive resource for understanding the human and mouse genomes. This phase III of the ENCODE Project has generated 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE and Roadmap Epigenomics data. The project has developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements (cCREs), covering 7.9% and 3.4% of their respective genomes. A web-based server (SCREEN; http://screen.encodeproject.org) provides flexible, user-defined access to this resource. The human genome contains DNA-encoded instructions that are read, interpreted, and executed by the cellular protein and RNA machinery to enable the diverse functions of living cells and tissues. The ENCODE Project aims to delineate precisely and comprehensively the segments of the human and mouse genomes that encode functional elements. Functional elements are defined as discrete, linearly ordered sequence features that specify molecular products or biochemical activities with mechanistic roles in gene or genome regulation. The ENCODE Project has applied a succession of state-of-the-art assays to identify likely functional elements with increasing precision across an expanding range of cellular and biological contexts. The project has incorporated new assays such as RNA-binding-protein localization and chromatin looping, increased the depths at which current assays interrogate reference cell lines, and collected data over a greatly expanded biological range, with an emphasis on primary cells and tissues. The project has also incorporated and uniformly processed the substantial data from the Roadmap Epigenomics Project that conform to ENCODE standards. The ENCODE Project has generated nearly 6,000 new experiments in phase III that have extended previous phases of ENCODE in order to define and annotate diverse classes of functional elements in the human and mouse genomes. The project has systematically integrated DNA accessibility and chromatin modification data to create a categorized registry of cCREs in both the human and mouse genomes. The project has also developed a new web-based interface called SCREEN to facilitate access to the human and mouse registries and to facilitate their application to diverse biological problems. The ENCODE Project has expanded the range of experimental data to provide new insights into genome organization and function, and catalysed new capabilities for deriving biological understandings and principles. The project has defined core gene sets that correspond to major cell types using extensive new maps of RNA transcripts in a broad range of primary cell types. The project has described an expansive new genomic compartment of DNA elements that encode recognition sites for RNA-binding proteins, providing new insights into post-transcriptional regulation. The project has deeply mapped the co-occupancy patterns of human transcription factors in reference cell types and connected these with key biological features of promoters and distal enhancers. The