Fatty acids play a central role among the epidermal lipids because of their considerable contribution to structural and functional features of the epidermis. They are important components of cell membranes, the intercellular stratum corneum lipids and the hydro lipid skin surface film. Additionally, endogenous fatty acids act as mediators of the epidermal cell proliferation and differentiation and therefore, lipid synthesis and also as mediators of inflammatory and immunological processes. The topical application of certain fatty acids leads to interactions at the structural and functional level. On the one hand, fatty acids may be of importance to restore a disturbed stratum corneum barrier. On the other hand, fatty acids are able to modulate dermal and transdermal drug transport. Mechanisms of the interaction between exogenous fatty acids and epidermal cells, especially keratinocytes, and effects on their proliferation and differentiation are currently under investigation or largely unknown, respectively.