The observation that defects of the cytosolic exonuclease TREX1 cause monogenic cGAS/STING-driven AGS and are associated with SLE extended the concept of DNA waste disposal to the cytosolic and/or nuclear compartments and raised questions about nature and origin of the immunogenic TREX1 DNA substrates that trigger disease in the absence of the nuclease. Here, TREX1 is linked to systemic lupus erythematosus.