Nuclear factor (NF)-κB transcription factors are pivotal regulators of innate and adaptive immune responses, and perturbations of NF-κB signaling contribute to the pathogenesis of immunological disorders. NF-κB is a well-known proinflammatory mediator, and its deregulated activation is associated with the chronic inflammation of autoimmune diseases. Paradoxically, NF-κB plays a crucial role in the establishment of immune tolerance, including both central tolerance and the peripheral function of regulatory T (Treg) cells. Thus, defective or deregulated activation of NF-κB may contribute to autoimmunity and inflammation, highlighting the importance of tightly controlled NF-κB signaling. This review focuses on recent progress regarding NF-κB regulation and its association with autoimmunity.