The functionality of proteins is greatly extended by a diverse array of post-translational modifications (PTMs), many of which are recognized by the immune system. Notably, a significant proportion of peptides presented to T cells by the major histocompatibility complex in vivo are post-translationally modified. Since the cellular mechanisms that introduce and control protein modifications can differ between health and disease, the associated changes in antigen presentation have the potential to alter immune responses. A number of such situations have been implicated with infection, inflammation, autoimmune disease, and cancer, and the investigation of PTMs that affect antigen recognition has provided insight in disease progression as well as raising prospects for novel approaches in immunotherapy.