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-kappaB) target genes within atherosclerotic lesions has led to the common-held belief that excessive NF-kappaB activity promotes and aggravates atherogenesis. However, mouse models lacking various proteins involved in NF-kappaB signaling have often resulted in conflicting findings, fueling additional investigations to uncover the molecular involvement of NF-kappaB and its target genes in atherogenesis. In this chapter we will review the role of the NF-kappaB-regulated, yet potent NF-kappaB inhibitory and anti-inflammatory gene A20/TNFAIP3 in atherogenesis, and highlight the potential use of its atheroprotective properties for the prevention and treatment of cardiovascular diseases.