Harlequin ichthyosis (HI) is an autosomal recessive congenital ichthyosis. HI is an extremely rare and most severe form of ichthyosis. The condition is caused by mutation of the ABCA12 gene resulting in impaired lipid transport in the outermost layer of the skin, the epidermis. During the neonatal period, harlequin ichthyosis manifests phenotypically as dramatic large polygonal plate-like scaling of the skin that cracks and can slough, revealing the underlying diffusely bright red skin. These thick skin plates can pull and distort facial features. The tightness of the skin can also pull on the eyes and mouth resulting in difficulties with closing these structures. The tightness also causes the eyes and the mouth to turn inside out resulting in ectropion and eclabium. Other features include hypoplasia of the fingers, malformation of the ears and nose, and alopecia. Affected neonates often do not survive, and mortality is commonly attributed to respiratory failure and/or sepsis. Clinical data obtained from 45 HI patients revealed 25 survivors and 20 deaths with an overall survival rate of only 56%. The ages of survivors ranged from 10 months to 25 years, and death usually occurred in the first 3 months. HI infants need to be cared for in a neonatal intensive care unit immediately after birth. Several harlequin neonates have survived. They tend to have severe erythroderma and fine scaling, even with optimal management. Survivors can suffer from recurrent skin infections from epidermal fissuring, contractures due to their tight skin, metabolic abnormalities, developmental delay, and pulmonary issues. High quality management of immediate newborn care may improve survival. Introduction of oral retinoids and its timing remain controversial, but frequent application of emollients to improve barrier function is critical.