Beside gene expression and translational control, which are relatively slow, PTM of proteins represents the major level of regulation, from very fast and reversible to slow or irreversible processes. PTMs affect protein structure and act as molecular switches, which regulate the interaction of proteins with DNA, cofactors, lipids, and other proteins. In the past few years, evidence for extensive crosstalk between PTMs has accumulated. The combination of different PTMs on protein surfaces can create a “PTM code,” which can be recognized by specific effectors to initiate/inhibit downstream events, only inducing/retaining a signal once the complementary incoming signals are present at the same time and place. Although MS-based proteomics has substantially improved our knowledge about PTMs, currently sensitive and dedicated analytical strategies are available only for few different types of PTM. Several recent studies focused on the combinatorial analysis of PTMs, but preferentially utilized peptide-centric bottom-up strategies might be too restricted to decipher complex PTM codes. Here, we discuss the current state of PTM crosstalk research and how proteomics may contribute to understanding PTM codes, representing the next level of complexity and one of the biggest challenges for future proteomics research.