Cellular function can be controlled through the gene expression program but often protein post translations modifications (PTMs) provide a more precisely and elegant mechanism. Key functional roles of specific modification events for instance during the cell cycle have been known for decades, but it has only been in the last ten years that mass spectrometry (MS)-based proteomics has begun to reveal the true extent of the PTM universe. In this overview for the special PTM issue in Molecular and Cellular Proteomics, we take stock of where MS-based proteomics stands in the large-scale analysis of protein modifications. For many PTMs, including phosphorylation, ubiquitination, glycosylation and acetylation, tens of thousands of sites can now be confidently identified and localized in the sequence of the protein. Quantitation of PTM levels between different cellular states is likewise established, with label-free methods showing particular promise. It is also becoming possible to determine the absolute occupancy or stoichiometry of PTMS sites on a large scale. Powerful software for the bioinformatic analysis of thousands of PTM sites has been developed. However, a complete inventory of sites has not been established for any PTM and this situation will persist into the foreseeable future. Furthermore, although PTM coverage by MS-based methods is impressive, it still needs to be improved, especially in tissues and in clinically relevant systems. The central challenge for the field is to develop streamlined methods for determining biological functions for the myriad of modifications now known to exist.