AbstractThe purpose of this review is to focus on determinants of skin barrier function in neonates at molecular and cellular levels. The skin barrier is critical in terms of water and gas exchanges during fetal life and undergoes rapid changes at birth, followed by a progressive maturation. Consequences of skin barrier disruption can be extremely detrimental or lethal, as shown in severe genetic epidermal defects. In this context, the fine‐tuned rapid adaptation from a liquid to a gaseous milieu is not fully understood. The stratum corneum provides an air‐liquid barrier, tight junctions in the granular layer provide a liquid‐liquid barrier, aquaporins represent a plumbing system for water‐glycerol as well as gas exchanges, and Langerhans cells are central to the immunological barrier. Acid mantle formation is essential for appropriate interaction between the skin and microbial symbionts. Temperature and pH regulate the key enzyme activities responsible for the integrity of the stratum corneum. Skin barrier permeability can be assessed noninvasively and simply with miniaturized devices measuring transepidermal water loss, where water flow is faster in cases of a damaged or functionally premature barrier. New avenues for therapeutic skin barrier research in neonates include a better delineation of the maturation of aquaporins in water balance and gas exchanges from fetal to neonatal life and a better understanding of the role of vernix caseosa, in particular, for the implantation of a healthy microbiote. Practical applications should be derived for caring for infant skin, particularly in fragile zones, such as the diaper area.