PADI mediated post-translational deimination/citrullination causes structural and functional changes in a wide range of target proteins; facilitating protein moonlighting, modifying protein-protein interaction, causing neo-epitope generation and epigenetic changes. PADs also regulate biogenesis of extracellular vesicles (EVs), which are key players in cellular communication, including through transfer of cargo, e.g., proteins, non-coding RNAs and genetic material. PADs and EVs are linked to many pathobiological processes, including in central nervous system injury, cancers, and infection. Pharmacological PAD inhibitors have shown great promise in several in vitro and in vivo CNS injury models, cancers, autoinflammatory disease and host-pathogen interactions. As circulating EVs can be used as non-invasive liquid biopsies, their specific cargo-signatures may allow for disease “fingerprinting” and aid early diagnosis and response to therapy. PAD homologues are also found in bacteria and parasites, and PAD inhibition has shown changes in EV release leading to increased sensitivity to antibiotics and reduced attachment to host cells. This talk discusses PADI-mediated modulation of EV signatures in pathobiology.