Post-translational modifications (PTMs) represent a major vehicle to diversify a cellular proteome, the inventory of all protein species in an organism. PTMs have critical roles in all the major cellular pathways and diseases. A protein can be potentially modified by more than 300 types of post-translational modifications, which are catalyzed by enzymes encoded by more than 5% of the genome in higher eukaryotes. A combination of a dozen PTM sites in a substrate protein could lead to more than a million possible protein structures with potentially different functions. Given the high abundance and diversities of PTMs, they are likely the most complex regulatory mechanisms in cells. Despite their critical roles in cells, little is known about their biology, except several most extensively studied PTMs. Functional characterizations of PTMs at the molecular level have been slow, largely due to a lack of suitable information infrastructure and technology infrastructure.