Incontinentia pigmenti (IP; OMIM#308300) is a rare multisystem genomic disorder (0.7/100.000), X linked and lethal in males, affecting the skin, but also other ectodermal tissues including the teeth, hair, nails, eyes, and Central Nervous System (CNS) in females. Beside the skin lesions that are always present in IP, other tissues can be differently affected and the most severe effect of the disease are those related to neurological and/or ocular impairment. IP is due to a mutation of the IKBKG/NEMO gene (Inhibitor of Kappa polypeptide gene enhancer in B-cells, Kinase Gamma/Nuclear Factor kappaB, Essential Modulator) located in the Xq28 region. 83% of cases have a recurrent deletion (IKBKGdel), removing exons 4–10 of the IKBKG/NEMO gene; 2% have non-recurrent genomic deletions in the IP locus; 9% have point mutations in the NEMO coding region; and 6% lack any known NEMO mutation. Most IKBKG/NEMO mutations are de novo; indeed, the IP syndrome is typically a sporadic condition (>70% of cases). IKBKG/NEMO encodes for NEMO/IKKgamma, a regulatory subunit of the inhibitor of the kappaB (IkB) kinase (IKK) complex required for canonical NF-kB pathway activation. All the defects associated to IP are caused by the NF-kB pathway dysfunction.