Nuclear factor-Kappa B (NF-kB) is an inactive transcription factor that became activated when translocate from cytoplasm to the nucleus, where it affects the expression of approximately 300 immunological, growth, and inflammatory genes. There are five members of the NF-kB family have been identified. There are two mechanisms for NF-kB activation: canonical and non-canonical signalling. NF-kB transcription factors are important regulators of both innate and adaptive immune responses, and abnormalities in NF-kB signalling lead to the development of immunological disorders. As a result of its activities during thymic selection, NF-kB is critical for maintaining immunological tolerance, both for negative selection of autoreactive T cells and for the selection and maintenance of Tregs. Rheumatoid arthritis, multiple sclerosis, thyroid illness, diabetes, asthma, systemic lupus erythematosus, and inflammatory bowel disease have all been associated to NF-kB. The goal of this review is to discuss about molecular mechanism of NF-kB and how it implicated in the pathogenesis of human diseases.