The skin is the largest organ of the body, covering about 1.7 m 2 and comprising approximately 10% of the total body mass of an average person. The primary function of the skin is to provide a barrier between the body and the external environment. This barrier protects against the permeation of ultraviolet (UV) radiation, chemicals, allergens and microorganisms, and the loss of moisture and body nutrients. In addition, the skin has a role in homeostasis, regulating body temperature and blood pressure. The skin also functions as an important sensory organ in touch with the environment, sensing stimulation in the form of temperature, pressure, and pain. While the skin provides an ideal site for administration of therapeutic compounds for local and systemic effects, it presents a formidable barrier to the permeation of most compounds. The mechanisms by which compounds permeate the skin are discussed later in this chapter, and methods to enhance permeation are described in Chapters 2–4. An understanding of the structure and function of human skin is fundamental to the design of optimal topical and transdermal dosage forms. The structure and function of healthy human skin is the main focus of this chapter. Physiological factors that can compromise the skin barrier function, including agerelated changes and skin disease, are also reviewed. Chapter 19 describes the current and future trends in the treatment of these and other skin diseases.