The NF-kappaB/Rel signaling system is a paradigm for gene activation in response to inflammatory and menacing stimuli. Given the growing body of evidence showing an important involvement of NF-kappaB for the onset of autoimmune diseases and different types of cancer, NF-kappaB is an important drug target for the adjuvant therapy of these diseases. Great efforts have been made for the development of highly specific NF-kappaB inhibitors, some of them being currently tested in phase II clinical trials. Here we discuss recent progress in the identification of druggable components of the NF-kappaB signaling system and the development and potential use of novel NF-kappaB inhibitors.