NF-κB/Rel transcription factors and IκB kinases (IKK) are essential for inflammation and immune responses, but also for bone-morphogenesis, skin proliferation and differentiation. Determining their other functions has previously been impossible, owing to embryonic lethality of NF-κB/Rel or IKK-deficient animals. Using a gene targeting approach we have ubiquitously expressed an NF-κB super-repressor to investigate NF-κB functions in the adult. Mice with suppressed NF-κB revealed defective early morphogenesis of hair follicles, exocrine glands and teeth, identical to Eda (tabby) and Edar (downless) mutant mice. These affected epithelial appendices normally display high NF-κB activity, suppression of which resulted in increased apoptosis, indicating that NF-κB acts as a survival factor downstream of the tumor necrosis factor receptor family member EDAR. Furthermore, NF-κB is required for peripheral lymph node formation and macrophage function.