DNA binding proteins, such as transcription factors, occupy cis-regulatory elements to regulate transcription of genes. When regulators are bound to DNA, the contacted nucleotides become protected from nucleases such as DNase I, leaving a ‘footprint’ of the bound regulatory sequence at single-nucleotide resolution. To provide detailed insight into the regulatory landscape of the human genome, Vierstra et al.1 have generated comprehensive maps of DNase I-footprints for 243 human samples, mostly primary cells and tissues from donors, and also cancer and immortalized cell lines, which represents a significant expansion of the previous phase of the ENCODE project. The authors integrated these data to define ~4.5 million consensus transcription factor-bound regulatory elements within the human genome. They also assigned likely transcription factors to these consensus footprints and were able to further characterize the fine structure of human regulatory regions. Furthermore, the authors show that disease- and trait-associated variants from genome-wide association studies are preferentially enriched within transcription factor footprints, thereby illustrating the potential of this extensive collection of regulatory elements to shed light on our understanding of how gene expression is regulated in health and disease.