Traditionally, most marketed drugs, irrespective of their route of delivery, have had relatively low molecular weights. Nowhere has this been more markedly true than in topical drug delivery. Historically, it was thought that to successfully permeate healthy skin, molecules must be of less than 500 Daltons, and must be moderately lipophilic with a low melting point and high potency. These rules, of course, were driven by the need to overcome the natural barrier function of the skin, which is designed to protect the body from physical, mechanical and chemical insults whilst further providing a barrier to endogenous water loss. The barrier function of the skin largely derives from the non-viable, thin (10–30 µm) cornified outermost layer, the stratum corneum. Dr Jon Lenn and Marc Brown at MedPharm try to answer the question as to whether large biologics can be delivered to/through the skin effectively enough for clinical relevance.