The skin is the largest and most accessible organ in the human body and, as such, it appears as the most convenient portal for drug delivery. However, the skin is also a formidable barrier which, while protecting us from physical, chemical, and immunological agents, requires appropriate technology for effective delivery. Today, the most effective administration method for large, lipophobic, and polar molecules continues to be hypodermic injection, which is associated with pain, needle phobia, and stick injury. As an alternative, a range of advanced strategies to overcome the skin barrier have been established over the last few decades including chemical enhancement, sonophoresis, iontophoresis, electroporation, thermal ablation, and mechanical approaches. Encouraged by the advances in nanotechnology, micro-and nanosystems have emerged as powerful tools to overcome the skin barrier, enabling significant advances on the existing methods. In particular, microneedle-and nanoparticle-assisted transdermal delivery has gained significant traction and will most likely have a strong impact in the field. In this review, the most recent progress in the field of transdermal delivery based on microneedle and nanoparticle delivery systems is discussed and examples of key therapeutic application are provided. Finally, a critical summary is presented alongside a vision for future research directions.