Please cite this paper as: IL‐6 Stimulates but is not essential for stratum corneum formation and permeability barrier development during gestation. Experimental Dermatology 2010; 19: e31–e36.Abstract:  The regulation of epidermal ontogenesis is a complex process. Previous studies have shown that cytokines (IL‐1, TNFα and IL‐6) regulate permeability barrier homeostasis in adult mice. Recently, we reported that IL‐1 and TNFα accelerate stratum corneum (SC) formation and permeability barrier development in foetal rodents. Here, we determined whether IL‐6 also regulates SC formation and permeability barrier development during late gestation. Using a rat skin explant model, we demonstrated that IL‐6 accelerates permeability barrier formation in a time‐ and dose‐dependent fashion. This acceleration of barrier formation is attributable to (a) accelerated lamellar membrane maturation, (b) formation of a multi‐layer SC and (c) enhanced expression of epidermal differentiation markers. When comparing epidermis of IL‐6‐deficient (knockout mice) and wild‐type foetal mice at days 16–18, we could not detect any abnormalities in either SC formation or the expression of differentiation markers in knockout (KO) mice. In parallel, the basal expression levels of IL‐6 mRNA in epidermis and IL‐6 protein in amniotic fluid were very low, with only a minimal change in IL‐6 receptor mRNA levels in epidermis of days 16–22 foetal mice. These low IL‐6 levels may account, at least in part, for the absence of epidermal abnormalities in IL‐6 KO mice. In conclusion, exogenous IL‐6 accelerates epidermal ontogenesis, but it is not essential for normal epidermal maturation.