The percutaneous absorption or transdermal permeation of drugs has gained considerable prominence in recent years through the development of transdermal systemic delivery systems and the related interest in the design and use of topical products. The present review discusses the phenomenon of percutaneous absorption in drug delivery and its importance in regard to the anatomy of skin, its physiological function, and biomechanical properties, as well as the physicochemical properties of the skin and the drug. The mathematical relationships and models used to describe the phenomenon of percutaneous absorption are also reported. The importance of these factors in optimizing percutaneous absorption or transdermal permeation of drugs for local or systemic effect is also discussed.