The purpose of the Encyclopedia of DNA Elements (ENCODE) Project is to discover and comprehensively map the functional elements of the genome. In the main paper1 reporting on the third phase of ENCODE, the authors describe the progress made towards a better understanding of the organization and activity of the human and mouse genomes through the application of more diverse methods to a broad range of primary human cell types and embryonic mouse tissues. A total of 5,992 experiments were performed to annotate transcribed elements, to explore the targets and motifs of RNA-binding proteins, to generate occupancy maps of transcription factors, to delineate accessible DNA regions in chromatin, to broadly map histone marks, histone variants and DNA methylation, to probe 3D genome organization, and to determine the timing of DNA replication. By integrating the epigenomic datasets and chromatin accessibility information, a Registry of human and mouse candidate cis-regulatory elements (cCREs) was built that contains a total of 926,535 human and 339,815 mouse cCREs and can be accessed through a browser (SCREEN; http://screen.encodeproject.org). The cCREs were classified into groups, including those displaying enhancer-like (87.4% of human cCREs) or promoter-like biochemical signatures (6.5% of cCREs). A subset of cCREs was validated using transgenic mouse enhancer-reporter assays. Together, the data from ENCODE 3 greatly improve the functional annotation of the human and mouse genomes and facilitate insights into development and disease.