Dysregulation of the transcription factor NF-κB causes chronic inflammation, autoimmunity, and malignancy. The zinc finger protein A20 is vital for regulating NF-κB signaling, so much so that mice lacking A20 die young of multiorgan failure and cachexia. Similar deficiencies have been seen in Crohn’s disease, rheumatoid arthritis, and other inflammatory diseases of humans. But how A20 works has remained unknown. Shembade et al. (see the Perspective by Sriskantharajah and Ley) have discovered that the A20 protein acts through the ubiquitin labeling system of the cell required for normal protein turnover and its lack prevents NF-κB recycling, resulting in chronic inflammation. A human T cell lymphotropic virus possesses an oncoprotein that subverts this pathway to the virus’s benefit by inhibiting A20 interactions with the ubiquitin pathway to promote NF-κB signaling and cell immortalization.