<p>Transdermal drug delivery system (TDDS) has become an efficacious alternative to conventional oral and injectable routes of administration with the benefit of non-invasive administration, controlled drug release, and improved patient compliance. However, despite the great developments, their clinical translation is still limited due to the strong barrier function of the stratum corneum, as well as the difficulty in the stability of the drug and the design of the formulation. This review provides an overview of next generation TDDS with a focus on the transition of preclinical developments to clinical applicability. Transdermal technologies are discussed considering the mechanism of action, limitations to performance and potential for clinical translation. The key approaches like microneedles, iontophoresis, ultrasound-assisted delivery and nanocarrier-based systems are referred to as having the potential to improve drug permeation and allow controlled delivery throughout skin. In addition, the review combines recent preclinical findings and clinical developments to help identify current gaps relevant to safety and scalability as well as regulatory issues. The rising therapeutic uses of TDDS such as their role in the management of chronic diseases, vaccination and regenerative medicine are also discussed. Overall, advanced transdermal approaches, especially ways of physical enhancement, are very promising in improving the delivery of complex therapeutics. Continued advancement in the design of materials, device design and evaluation approaches will be necessary to the successful transfer of TDDS from the laboratory into the clinic.</p> Graphical Abstract <p></p>