To achieve an efficient skin penetration of most compounds it is necessary to overcome the barrier function of the skin, provided mainly (but not only) by the stratum corneum. Among various strategies used or studied to date, chemical penetration enhancers are the most frequently employed with one of the longest histories of use. There is a multitude of agents described as penetration enhancers, and they present varying properties and structures. In this manuscript, we aim to provide a brief overview of traditional enhancers and some of their properties, focusing on the benefits of combination of chemical enhancers and on selected novel compounds that have shown promise to increase drug delivery into/across the skin.