The Encyclopedia of DNA Elements (ENCODE) Project has expanded its analysis of the human and mouse genomes to better understand the elements that specify RNAs and proteins and govern their production. Phase III of the project has produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. The ENCODE data portal provides access to all data, including phase II ENCODE and Roadmap Epigenomics data. A registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements (ccREs) has been developed, covering 7.9% and 3.4% of their respective genomes. A web-based server, SCREEN, facilitates access to this resource and its application to diverse biological problems. The ENCODE data and registry provide a comprehensive resource for understanding the organization and function of the human and mouse genomes. The project has expanded its scope by incorporating new assays, increasing the depth of current assays, and collecting data over a broader biological range, with a focus on primary cells and tissues. The ENCODE Encyclopedia includes ground-level and integrative-level annotations, and the SCREEN tool integrates all levels of annotations and raw data for visualization in the UCSC genome browser. The registry of ccREs is classified into three major groups based on function-associated signatures: active and poised enhancer-like elements, active and poised promoter-like elements, and CTCF-only elements. The distribution and evolutionary conservation of ccREs are similar to those of DNase I hypersensitive sites, and they are highly congruent with other ENCODE data types. Initial functional assessments of predicted enhancers in mid-gestation mouse embryos show that at least one-third of the predicted enhancers are active in vivo. The ENCODE Encyclopedia aims to help researchers decode the molecular mechanisms underlying genetic traits and diseases, and it is expected to provide a powerful tool for interpreting genome-wide association studies.The Encyclopedia of DNA Elements (ENCODE) Project has expanded its analysis of the human and mouse genomes to better understand the elements that specify RNAs and proteins and govern their production. Phase III of the project has produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. The ENCODE data portal provides access to all data, including phase II ENCODE and Roadmap Epigenomics data. A registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements (ccREs) has been developed, covering 7.9% and 3.4% of their respective genomes. A web-based server, SCREEN, facilitates access to this resource and its application to diverse biological problems. The ENCODE data and registry provide a comprehensive resource for understanding the organization and function of the human and mouse genomes. The project has expanded its scope by incorporating new assays, increasing the depth of current assays, and collecting data over a broader biological range, with a focus on primary cells and tissues. The ENCODE Encyclopedia includes ground-level and integrative-level annotations, and the SCREEN tool integrates all levels of annotations and raw data for visualization in the UCSC genome browser. The registry of ccREs is classified into three major groups based on function-associated signatures: active and poised enhancer-like elements, active and poised promoter-like elements, and CTCF-only elements. The distribution and evolutionary conservation of ccREs are similar to those of DNase I hypersensitive sites, and they are highly congruent with other ENCODE data types. Initial functional assessments of predicted enhancers in mid-gestation mouse embryos show that at least one-third of the predicted enhancers are active in vivo. The ENCODE Encyclopedia aims to help researchers decode the molecular mechanisms underlying genetic traits and diseases, and it is expected to provide a powerful tool for interpreting genome-wide association studies.