NF-kappaB comprises a family of transcription factors that are critically involved in various inflammatory processes. In this paper, the role of NF-kappaB in inflammation and atherosclerosis and the regulation of the NF-kappaB signaling pathway are summarized. The structure, function, and regulation of the NF-kappaB inhibitors, IkappaBalpha and IkappaBbeta, are reviewed. The regulation of NF-kappaB activity by glucocorticoid receptor (GR) signaling and IkappaBalpha sumoylation is also discussed. This paper focuses on the recently reported regulatory function that adipocyte enhancer-binding protein 1 (AEBP1) exerts on NF-kappaB transcriptional activity in macrophages, in which AEBP1 manifests itself as a potent modulator of NF-kappaB via physical interaction with IkappaBalpha and a critical mediator of inflammation. Finally, we summarize the regulatory roles that recently identified IkappaBalpha-interacting proteins play in NF-kappaB signaling. Based on its proinflammatory roles in macrophages, AEBP1 is anticipated to serve as a therapeutic target towards the treatment of various inflammatory conditions and disorders.