A battery of proinflammatory agents triggers the activation of NF-kappaB. This inducible transcription factor participates in the expression of an exceptionally large number of target genes, many of them contributing to the regulation of innate and adaptive immunity. Since some target genes also function as NF-kappaB activators, activation of this transcription factor allows the establishment of a signal amplification loop. Dysregulation of the NF-kappaB system and hyperactivated expression of inflammatory mediators are often found in association with some autoimmune diseases, which occur upon mounting of the adaptive immune response against self-antigens. In this review we summarize the relevance of aberrant NF-kappaB signaling for the development and perpetuation of some autoimmune diseases such as rheumatoid arthritis, diabetes mellitus type 1 and Crohn's disease. The assets and drawbacks of systemic or cell-type specific NF-kappaB inhibitors and their potential use in therapy of autoimmune diseases are critically discussed.