The identification and characterization of cis-regulatory elements such as promoters, enhancers, silencers, and insulators is essential for the understanding of transcription regulation. However, it is difficult to achieve this in a systematic manner. When cis-regulatory elements are activated by transcription factor binding in place of nucleosomes, DNA becomes accessible to nucleases such as DNase I. DNase I-hypersensitive sites (DHSs) can be used to precisely identify regulatory sequences in the genome. Here, Meuleman et al.1 present a comprehensive collection of high-resolution maps of DHSs obtained from 733 human samples, comprising the major organ systems — a significant increase in sample size from the previous phase of ENCODE. These datasets were integrated into a unified index for human genomic regulatory elements that encompasses both common and cell-type specific regulatory patterns. The authors were able to distil the biological activation patterns of DHSs into a simple vocabulary and assign a regulatory ‘barcode’ to each DHS. This barcode in turn allows for the regulatory annotation of protein-coding and non-coding RNAs. Importantly, the authors also showed that DHS barcodes allow the enhanced annotation and prioritization of genetic variants that have been associated with disease and heritable traits. This extended DHS repertoire will help to expand our understanding of how gene expression is regulated, and how it is regulated in human health and disease.