Post translational modification (PTM) of histones has long been associated with epigenetic regulation. Although genomic approaches have established correlation between a handful of histone PTMs and transcriptional states, only recently have advancements in proteomics provided the tools necessary to study histone proteins and their relevant modifications in this context. Using mass spectrometry, researchers have demonstrated the ability to determine the full repertoire of histone PTMs, their residue specific location, the combinations in which they exist, and the proteins that interact with these combinations. Moving forward it will be imperative to develop novel approaches that combine proteomic and genomic technologies to determine the functional significance of these combinations of modifications. Assays with increased specificity will resolve more focused biological questions and determine to what extent, and by what mechanisms, histones influence transcription.