The skin is the largest single organ of the human body and acts as a barrier to the external environment. This chapter describes the detailed structure of the skin and explains the issues involved in using intact, healthy skin as a portal for systemic drug delivery. The stratum corneum, due to its unique and highly organised structure, is identified as the primary barrier to transdermal drug delivery, with passive drug diffusion along a concentration gradient being the primary method of permeation across the barrier. This, in turn, dictates the need for conventional transdermal drug delivery to employ drugs with sufficient lipophilicity to allow permeation via an intercellular pathway through the lipids of the stratum corneum. The alternative pathway, through skin appendages, is also described, along with its limitations as a major route for nonfacilitated transdermal delivery. Given the advantages of transdermal delivery for the patient, there is a clear need to extend the utility of the transdermal route such that it is accessible for a wider range of pharmacologically active agents. Due to the limitations imposed by conventional transdermal systems, notably the restriction to lipophilic permeants, a range of facilitation technologies are described that may be used to overcome the skin barrier in cases where the required drug does not have ideal physicochemical properties for passive permeation through the skin barrier. Technologies considered include cryopneumatic and photopneumatic approaches, sonophoresis (low‐frequency ultrasound), iontophoresis, electroporation, jet injection and microneedles.