Lysine deacetylase inhibitors (KDACis) are approved drugs for cutaneous T-cell lymphoma (CTCL) and multiple myeloma. The drugs lead to increasing acetylation levels of histones and other proteins, altered gene expression, and cell death. To characterize the mechanisms of action of these drugs in more detail, we systematically measured dose-dependent drug-induced changes in protein expression, acetylation, and phosphorylation in response to 21 clinical and pre-clinical KDACis. The resulting 872,000 dose-response curves revealed, for instance, poor selectivity of HDAC1, 2, 3, and 6 inhibitors in cells, strong cross-talk between acetylation and phosphorylation pathways, localization of most drug-responsive acetylation sites to intrinsically disordered regions (IDRs), an underappreciated role of acetylation in protein structure and a shift in EP300 protein abundance between the cytoplasm and the nucleus. This comprehensive dataset serves as a resource for the investigation of the molecular mechanisms underlying KDACi action in cells and can be explored online in ProteomicsDB.