Understanding protein function is at the heart of experimental biology. Perhaps one of grandest contemporary challenges in this area is to catalogue and then functionally characterize protein post-translational modifications (PTMs). Modern analytical techniques reveal that most, if not all, proteins are modified at some point; it is nature’s way of imposing functional diversity on a polypeptide chain. Understanding the structural and functional consequences of all these PTMs is a devilishly hard problem. While standard molecular biology methods are of limited utility in this regard, modern protein chemistry has provided powerful methods that allow the detailed interrogation of protein PTMs. In this lecture, I will highlight the use of high-throughput methods for studying the role of PTMs in regulating aspects of chromatin biology. In particular, I will discuss how histone modifications, and cancer-associated mutations, impact the activity of chromatin modifying enzymes and chromatin remodeling machines.