The skin, and in particular the epidermis, is a physical barrier that protects the body from external threats and is critically involved in immune reactivity. Professional antigen-presenting cells, such as epidermal Langerhans cells and dermal dendritic cells, are gaining prominence as principal players orchestrating the decision between immunity and tolerance. A focus of research interest in recent years has been the investigation of these cells in mammalian prenatal skin. In this review, we will compare the recent progress in dissecting the phenotype and functional role of antigen-presenting cells in the developing human and mouse skin before birth and perinatally, and will discuss how this knowledge improves our understanding of the level of immunocompetence of the skin in utero.