Reversible enzymatic modifications of protein side-chains, also known as post-translational modifications or PTMs, confer complexity to biological systems by dynamically regulating the location, structure, and activity of proteomes. Elucidating the mechanistic contributions of post-translationally modified proteins to key cellular processes, such as gene transcription, is critical for understanding normal human development and to identify new therapeutic targets in diseases arising from the misregulation of PTMs. To accomplish these goals, we apply a seamless combination of chemical and molecular biological tools to investigate uniformly modified proteins in well-defined biophysical and biochemical systems. This enables us to elucidate the structure, function, and regulation of two important families of nuclear proteins – histones and transcription factors – that are implicated in cancers of the skin, breasts, lungs and brain.