The cytosolic antibody receptor and RING E3 ligase TRIM21 targets intracellular, antibody-coated immune complexes for degradation and activates the immune system. Here we review how TRIM21 degrades diverse targets and how this activity can be exploited in molecular biology and for the development of new therapeutics. In addition, we compare what is known about TRIM21's mechanism to other TRIM proteins and RING E3 ligases.