The stratum corneum is seen as the main physical barrier that prevents the entry of solutes into the skin and manages the egress of water and endogenous molecules from the body. It is the thin outermost layer of the skin consisting of corneocytes (flattened, closely packed, and interdigitated “dead” cells packed with keratin) embedded in a highly organized, dense lipid intercellular space (1,2). The skin also has other barrier and support properties including immunological, metabolic, cushioning, sensing, and temperature control. In addition, the blood and lymphatics in the skin enable the removal of absorbed and skin metabolized solutes into the systemic circulation for further detoxification and excretion. The other distinct skin layers involved in providing these functions are the viable epidermis, dermis, and hypodermis. In this chapter, we first review the morphology of the viable skin layers and the skin appendages. We then examine the role the substructures below the stratum corneum may play in the physical and metabolic barrier properties of the skin and in the removal of solutes absorbed into the skin.