A pivotal transcription factor influencing both gene expression and apoptosis is the nuclear factor-kappa B (NF-κB). NF-κB is a central regulator of inflammation by inducing adhesion molecules and other pro-inflammatory components. In ischemia/reperfusion injury, NF-κB upregulates the genes encoding these molecules. Attenuating the process could be important in decreasing myocardial infarct size or diminishing the likelihood of acute renal failure when the heart or kidneys are subject to ischemia. In this issue, Lutz et al. [1] show that an endogenous protector can suppress the pro-inflammatory activation of NF-κB. This protector is the NF-κB-induced zinc finger regulator, termed A20. The authors first studied human endothelial cells that were exposed to 1% O2 for 4 h followed by reoxygenation. They observed that E-selectin, vascular cell adhesion molecule, and interleukin (IL-8) expression were transiently increased, accompanied by sustained A20 expression. The authors next used an adenovirus to introduce A20 and found that the endothelial cells exhibited blunted NF-κB activation of the above-mentioned genes in response to hypoxia/re-oxygenation. They next subjected rats to renal ischemia/reperfusion by 45-min renal pedicle clamping. Pretreatment of the animals with adenovirus carrying A20 reduced renal inflammation and injury. The authors concluded that A20 maintains homeostasis in kidneys exposed to ischemia/reperfusion, a form of endogenous damage control. What is A20 [2]? A20 is a cytoplasmic protein that contains an N-terminal ovarian tumor (OTU) domain and seven novel zinc finger structures with a characteristic CysXaa2–4-Cys-Xaa11-Cys-Xaa2–Cys motif. What are zinc fingers? A zinc finger is a protein domain that can bind to DNA. A zinc finger consists of two anti-parallel β sheets and an α-helix. The zinc ion is crucial for the stability of this domain type; in the absence of the metal ion the domain unfolds, since it is too small to have a hydrophobic core. Zinc fingers are important in regulation because, when interacted with DNA and zinc ion, they provide a unique structural motif for DNA-binding proteins. The structure of each individual finger is highly conserved and consists of about 30 amino acid residues, constructed as a ββα-fold and held together by a zinc ion. The α-helix occurs at the C-terminal part of the finger, while the β-sheet occurs at the N-terminal part. Many transcription factors, regulatory proteins, and other proteins that interact with DNA contain zinc fingers, as does A20. These proteins typically interact with the major groove along the double helix of DNA in which case the zinc fingers are arranged around the DNA strand in such a way that the α-helix of each finger contacts the DNA, forming an almost continuous stretch of α-helices around the DNA molecule. How does A20 regulate NF-κB and influence apoptosis [2, 3]? To deal with this complicated question, a prototype model of NF-κB and common activators should be presented first (Fig. 1). Perhaps, the best model of NF-κB activation, although by no means the only model, is via tumor necrosis factor (TNF) and members of the IL-1/toll receptor family. TNF binds to its receptor (TNFR1) and activates the recruitment of TNF-receptor-associated factor (TRAF2) and the receptor-interacting protein (RIP). This combination binds to the TNFR via the adapter protein known as TNFRSF1A-associated via death domain (TRADD). TRADD in turn recruits Fas-associated protein with death domain (FADD), which is an adaptor molecule J Mol Med (2008) 86:1297–1300 DOI 10.1007/s00109-008-0411-6