- The development of topical and transdermal drug delivery systems has aimed at overcoming the remarkably efficient barrier property of human skin by nontoxic and nonirritant methods. Numerous chemical and physical approaches have been investigated to overcome the skin's formidable barrier function. This article reviews two types of drug delivery approaches currently under investigation, which aim to increase drug permeability into and through the skin, by using fatty acid conjugates. The first approach uses fatty-acid conjugates as chemical enhancers for topical drugs while avoiding irritation, which is usually caused by the conventional use of free fatty acids. The second approach uses a conjugation of fatty acids to hydrophilic drug molecules to create effective topical prodrugs. The polyunsaturated fatty acid (PUFA) ester prodrugs for dermal delivery may be particularly promising and more advantageous by playing a role of "mutual prodrugs." This article presents an overview of the ongoing research on fatty acid conjugates for dermal application. The concepts, potential uses, limitations as well as their safety considerations are described.