Human skin not only functions as a permeation barrier (mainly due to the stratum corneum layer), but it also provides a unique delivery pathway for therapeutic and other active agents. Skin is a widely used route of delivery for local and systemic drugs and is useful as a route for their delivery as nanoparticles. The skin behaves as a natural physical barrier against particle penetration, but there are opportunities to deliver therapeutic nanoparticles, especially in diseased skin and to the openings of hair follicles. These compounds penetrate via intercellular, intracellular and transappendageal routes, resulting in topical delivery (into skin strata) and transdermal delivery (to subcutaneous tissues and into the systemic circulation). Active and passive permeation enhancement methods have been widely used to increase cutaneous penetration. Recent literature has demonstrated that nanoparticles-based topical delivery systems can be successful in treating skin conditions as they combine the advantages of both the nano sized drug carriers and the topical approach.