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We present a modified approach of chromatin immuno‐precipitation followed by sequencing (ChIP‐Seq), which relies on the direct ligation of molecular barcodes to chromatin fragments, thereby permitting experimental scale‐up. With Bar‐ChIP now enabling the concurrent profiling of multiple DNA–protein interactions, we report the simultaneous generation of 90 ChIP‐Seq datasets without any robotic instrumentation. We demonstrate that application of Bar‐ChIP to a panel of Saccharomyces cerevisiae chromatin‐associated mutants provides a rapid and accurate genome‐wide overview of their chromatin status. Additionally, we validate the utility of this technology to derive novel biological insights by identifying a role for the Rpd3S complex in maintaining H3K14 hypo‐acetylation in gene bodies. We also report an association between the presence of intragenic H3K4 tri‐methylation and the emergence of cryptic …