Incontinentia pigmenti is an uncommon X-linked dominant genodermatosis primarily affecting females. Its hallmark is a unique skin eruption that presents in infancy along the lines of Blaschko and evolves through four stages: inflammatory, verrucous, hyperpigmented, and atrophic. Other persistent findings of the disease include alopecia and dental anomalies. In a minority of cases, serious ophthalmologic and neurological alterations may occur. Mutations in the NF-κB essential modulator (NEMO) that lead to an inability to activate the NF-κB pathway produce IP. Less deleterious mutations in NF-κB essential modulator give rise to hypohidrotic ectodermal dysplasia with immune deficiency in affected males, a related but distinct phenotype. These recent discoveries provide insight into the crucial role of NF-κB function in regulating the developmental, inflammatory, immune, and anti-apoptotic responses of the skin and other organs.