Cardiovascular disease (CVD) is the biggest killer in the Western World despite significant advances in understanding its molecular underpinnings. Chronic inflammation, the classical hallmark of atherogenesis is thought to play a key pathogenic role in the development of atherosclerotic lesions from initiation of fatty streaks to plaque rupture. Over-representation of mostly pro-inflammatory nuclear factor kappa B (NF-KB) target genes within atherosclerotic lesions has led to the common-held belief that excessive NF-KB activity promotes and aggravates atherogenesis. However, mouse models lacking various proteins involved in NF-KB signaling have oftenresulted in conflicting findings, fueling additional investigations to uncover the molecular involvement ofNF-KB and its target genes in atherogenesis. Tn this chapter we will review the role of the NF-KB-regulated, yet potent NF-KB inhibitory and anti-inflammatory gene A20/TNF AIP3 in atherogenesis, and highlight the potential use of its atheroprotective properties for the prevention and treatment of cardiovascular diseases.