The regulation of gene expression by transcription factors is fundamental to the phenotype of all cells. The activated phenotype of cells engaged in inflammatory processes is characterized by induced expression of a diverse set of genes, including cytokines, enzymes and cell adhesion molecules. A relatively small number of inducible transcription factors, particularly NF-kappaB, AP-1, NFATs and STATs, are responsible for the expression of a wide variety of inflammatory phenotypic characteristics and therefore play a central role in the pathogenesis of rheumatic diseases. Each of these transcription factors can be modified by existing anti-rheumatic and anti-inflammatory drugs, although adverse effects and limited efficacy remain problems. The future development of therapeutic agents with specificity for transcription factors, especially NF-kappaB, might lead to safer and more effective treatment.