Mammalian skin provides a relatively efﬁcient barrier to the ingress of exogenous materials and the egress of endogenous compounds, particulary water. Loss of this vital function results in death from dehydration. Compromised function is associated with complications seen in several dermatological disorders. Stratum corneum intercellular lipid domains form a major transport pathway for penetration (1-4). Perturbation of these lamellar lipids causes skin permeation resistance to fall and has implicated their crucial role in barrier function. Indeed, epidermal sterologenesis appears to be modulated by the skin’s barrier requirements (5). Despite the fact that the skin is perhaps the most impermeable mammalian membrane, it is permeable to a degree, that is, it is semipermeable; as such, the topical application of pharmaceutical agents has been shown to be a viable route of entry into the systemic circulation as well as an obvious choice in the treatment of dermatological ailments. Of the various approaches employed to enhance the percutaneous absorption of drugs, occlusion (deﬁned as the complete impairment of passive transepidermal water loss at the application site) is the simplest and perhaps one of the most common methods in use. In this chapter we have summarized the literature to evaluate the effect of occlusion on the percutaneous absorption of topically applied compounds and to look at how certain compound physicochemical properties (such as volatility, partition coefﬁcient, and aqueous solubility) may predict what effect occlusion may have.