A novel analysis published in Nature Genetics reveals >60,000 common variants that directly influence transcription factor occupancy and regulatory DNA accessibility in vivo. The authors systematically combined regulatory DNA genotyping with allelically resolved genomic DNase I hypersensitive site sequencing (DNase-seq) of more than 114 cell and tissue types and states sampled from 166 individuals, to identify regulatory variants that directly influence the chromatin architecture of individual regulatory regions in an allele-specific manner. Maurano et al. then created in vivo profiles of the variation affecting diverse transcription factor families to discriminate nearly 500,000 common regulatory variants that may affect transcription factor occupancy across the human genome. The results highlight that genetic variation in regulatory DNA is predominantly interpreted in a cell type-specific fashion and provide a new foundation for the analysis and interpretation of common disease- and trait-associated variants that localize within regulatory DNA.