The transcription factor NF-κB regulates the expression of numerous genes controlling the immune and stress responses, inflammatory reaction, cell adhesion, and protection against apoptosis. Incontinentia pigmenti (IP) is the first genetic disorder to be ascribed to NF-κB dysfunction. IP is an X-linked dominant genodermatosis antenatally lethal in males. A complex rearrangement of the NEMO (NF-κB essential modulator) gene accounts for 85% of IP patients, and results in undetectable NEMO protein and absent NF-κB activation. On the other hand, hypohidrotic/anhidrotic ectodermal dysplasia (HED/EDA) has been ascribed to at least three genes also involved in NF-κB activation: ectodysplasin (EDA1), EDA-receptor (EDAR) and EDAR-associated death domain (EDARADD). During hair follicle morphogenesis, EDAR is activated by ectodysplasin, and uses EDARADD as an adapter to build a signal transducing complex that leads to NF-κB activation. Hence, several forms of HED/EDA also result from impaired activation of the NF-κB cascade. Finally, hypomorphic NEMO mutations have been found to cause anhidrotic ectodermal dysplasia with immunodeficiency (EDA–ID), whilst stop codon mutations cause a more severe phenotype associating EDA–ID with osteopetrosis and lymphoedema (OL–EDA–ID). The immunological and infectious features observed in patients result from impaired NF-κB signalling, including cellular response to LPS, IL-1β, IL-18, TNF-α, Tlr2 and CD40 ligand. Consistently, mouse knockout models have shown the essential role of NF-κB in the immune, inflammatory and apoptotic responses. Unravelling the molecular bases of other forms of EDA not associated with mutations in NEMO will possibly implicate other components of the NF-κB signalling pathway.