Transdermal drug delivery has been intensively studied over the last two decades because of the many advantages offered by this route of administration. However, the number of drugs used in transdermal drug delivery systems has been somewhat limited, in part resulting from the formidable barrier to drug permeation presented by the upper layer of the skin, the stratum corneum. In order to overcome this, different strategies have been implemented to render the skin more permeable to drugs. These strategies include both chemical and physical approaches. In this review, we outline the enhancing activities and mechanisms of action of some of the more extensively studied chemical penetration enhancers (oxazolidinones, propylene glycol, and epidermal enzymes). In addition, we discuss novel physical strategies, such as the use of microneedles or electroporation.