Nuclear factor kappa B (NF-κB) is an important transcription factor. Aberrant regulation of the NF-κB pathway is frequently observed in a number of major ailments such as cancer and inflammatory diseases. Hence NF-κB modulators have been intensely pursued for their potential therapeutic applications. Numerous reviews have described recent progress in the development of these agents. More recently, a variety of structurally and functionally novel small molecules, identified through high-throughput screens conducted within the Molecular Libraries Screening Center Network (MLSCN) of the NIH Roadmap for Medical Research, have been added to the current list of NF-κB regulators. This review will discuss the inhibitors and activators newly discovered by Columbias Molecular Libraries Screening Center (MLSC) using a well-designed and stable cellular assay.