NF-kappaB is an inducible transcription factor that is controlled by the signal activation cascades. NF-kappaB controls a number of genes involved in immuno-inflammatory responses, cell cycle progression, inhibition of apoptosis, and cell adhesion, thus promoting chronic inflammatory responses. In fact, NF-kappaB is constitutively activated in some rheumatic conditions such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Interestingly, a number of anti-RA compounds have been shown to exhibit anti-NF-kappaB activities. In addition, NF-kappaB activation has been linked to carcinogenesis and its constitutive activation has been demonstrated in some cancers and leukemias. These findings have substantiated the long-standing proposal of the link among chronic inflammation, autoimmunity, and carcinogenesis by molecular terms. In this review, I have attempted to overview the pathologic involvement of NF-kappaB in rheumatic diseases and discuss the feasibility of a therapeutic strategy with NF-kappaB and its signaling cascade as novel molecular targets.