One of the strategies developed by a number of bacteria and viruses to favor their replication consists in modifying host cellular proteins at the post-translational level, thereby altering their localization, interaction, activation and/or turnover. Among these, the post-translational modification (PTM) named citrullination/deimination is the process where the guanidinium group of an arginine is hydrolyzed to form citrulline, a non-genetically encoded amino acid. This PTM is catalyzed by the calcium-dependent protein arginine deiminase (PAD) family of enzymes, which in humans is composed of five isoforms (PADs 1-4 and 6), with different tissue-specific expression and substrate specificities. Although aberrant citrullination has been detected in several inflammatory conditions, suggesting that it may play a pathogenic role in inflammation-related diseases, a direct correlation between citrullination and viral infections has only recently emerged. Here, I’ll describe the more recent results from our group that led to the definition of the citrullination profile, the specific expression of different PADs, and the citrullinated substrates in the course of infections with both DNA and RNA viruses. In addition, the results obtained with a large panel of PAD inhibitors, describing their antiviral activity against viruses from the Herpesviridae and Coronaviridae families in a wide variety of cell lines, will be discussed.