Although cancer was long considered a genetic disease, the contribution of epigenetics to various aspects of cancer biology is now being increasingly recognized. In particular, aberrations in the deposition and maintenance of histone post-translational modifications (PTMs) can result in the inappropriate expression or silencing of genes, potentially leading to cancer. Here, we applied quantitative mass-spectrometry-based technologies to study histone PTMs and variants in different breast cancer subtypes, with a special focus on triple-negative breast cancers (TNBCs), which comprise a heterogeneous group of tumors lacking well-defined molecular targets and targeted therapies.