The nuclear factor-κB (NF-κB) family of transcription factors consists of the five members; RelA, RelB, c-Rel, NF-κB1 and NF-κB2, which form homodimers or heterodimers and act via two distinct pathways known as the canonical and non-canonical pathways. A multitude of intracellular molecules participates in the positive and negative regulation of these pathways. Under physiological conditions, signaling via NF-κB plays an important role in the establishment of immunological self-tolerance in the bone marrow and thymus, and defects in these pathways can cause manifestations of autoimmunity. Under pathological conditions, aberrantly upregulated signaling cascades, including NF-κB, result in the expression of many proinflammatory molecules. Indeed, NF-κB pathways are activated in peripheral blood cells and the diseased organs of patients with systemic lupus erythematosus and antiphospholipid syndrome, as well as in animal models thereof. Recent in vitro and in vivo studies suggest that key molecules in the NF-κB pathways represent promising therapeutic targets.