TRIM21 is a recently discovered mammalian Fc receptor and E3 ubiquitin ligase expressed in the cytosol of all cells. The highest affinity IgG receptor in man[1], it mediates an intracellular humoral response against antibody-opsonized pathogens that invade the cytosol during infection[2]. Upon detection, TRIM21 initiates a programme of ubiquitination[3] that recruits cellular degradation machinery, which catalyse the disassembly and destruction of cytosolic virions to prevent their replication. This rapid virion destruction also exposes the genomes of RNA and DNA viruses, allowing TRIM21 to potentiate the activity of RIG-I, cGAS and the inflammasome and induce a potent antiviral state[4, 5]. TRIM21 is effective against diverse viruses but also bacteria and proteopathic agents like tau. In my talk, I will summarize key aspects of TRIM21 biology and focus on recent work showing how its ubiquitination and inflammatory signaling is regulated and how we have repurposed its unique activity to perform targeted protein depletion[6]. This latter technology, called ‘Trim-Away’, uses off-the-shelf antibodies to rapidly and acutely degrade cellular proteins in diverse cells[7].