This chapter describes the physiology and structure of the skin, emphasising and focusing on the skin's main barrier to permeation – the stratum corneum – and how its structure and nature, compared to other regions and layers of the skin, results in a substantial barrier to both the ingress of exogenous materials and the egress of materials such as water. Mechanisms of transport across the stratum corneum and underlying tissues are discussed, including the relative contributions of the transappandageal, intercellular and intracellular pathways to the process of percutaneous absorption, and how regional variation influences absorption. Strategies to enhance absorption are discussed: this will consider, for example, classical formulation methods, such as the use of solvents and penetration enhancers to enhance absorption and physical methods of enhancement, such as iontophoresis, sonophoresis and microneedle-based technologies. These subjects are addressed in described in a manner appropriate for contextualisation to the wider themes of this book.