Arginine methylation is a common post-translational modification functioning as an epigenetic regulator of transcription and playing key roles in pre-mRNA splicing, DNA damage signaling, mRNA translation, cell signaling, and cell fate decision. Recently, a wealth of studies using transgenic mouse models and selective PRMT inhibitors helped define physiological roles for protein arginine methyltransferases (PRMTs) linking them to diseases such as cancer and metabolic, neurodegenerative, and muscular disorders. This review describes the recent molecular advances that have been uncovered in normal and diseased mammalian cells. Arginine methylation is a common modification regulating epigenetics and playing key roles in pre-mRNA splicing, translation, DNA damage, cell signaling, and cell fate decision. Blanc and Richard highlight studies that use transgenic mouse models and selective PRMT inhibitors to define physiological roles for protein arginine methyltransferases, linking them to diseases.