Transcription factor nuclear factor-kappaB (NF-kappaB) and its target genes are involved in the pathogenesis of atherosclerosis, in addition to many other diseases. Monocyte recruitment into subendothelial space is primarily mediated by NF-kappaB-dependent gene expression, and this event is a crucial milestone, because it is nearly impossible to reverse the progression of the lesion after this point. Recent advances in our understanding of atherosclerosis as a disease of childhood enforces the necessity of developing novel approaches for prevention and treatment. Here, the authors address NF-kappaB as a major therapeutic target, especially for preventive measures, in the light of two main hypotheses of atherosclerosis: oxidation and inflammation.