Transdermal drug delivery has made significant contributions to medical practice but has yet to fully realize its potential as an alternative to oral administration and injections. First-generation systems, which rely on the skin's natural permeability, have been widely used for small, lipophilic drugs. Second-generation systems use chemical enhancers, iontophoresis, and non-cavitational ultrasound to improve delivery, while third-generation systems target the stratum corneum using microneedles, thermal ablation, and electroporation, enabling delivery of macromolecules and vaccines. Transdermal delivery is attractive due to its non-invasive nature, long-term release capability, and improved patient compliance. It has been used for drugs like estradiol, fentanyl, and testosterone, and for vaccines. Over the past few decades, the number of transdermal delivery systems has increased significantly, with more than one billion patches produced annually. Transdermal delivery offers advantages over oral and injectable routes, including avoiding first-pass metabolism and reducing pain and infection risks. However, it is limited to drugs with specific molecular properties. Recent advancements in chemical enhancers, iontophoresis, and physical methods have expanded the range of deliverable drugs, including hydrophilic compounds and vaccines. Third-generation systems, such as microneedles and thermal ablation, have shown promise in delivering macromolecules and vaccines. These methods target the stratum corneum, enhancing permeability without damaging deeper tissues. Clinical trials have demonstrated the safety and efficacy of these approaches, with microneedles showing particular potential for vaccine delivery. Future developments in transdermal delivery aim to improve drug delivery efficiency, safety, and cost-effectiveness. Advances in chemical enhancers, iontophoresis, and physical methods are expected to further expand the range of deliverable drugs and improve patient outcomes. The field is poised to have a significant impact on medicine through continued innovation and clinical application.Transdermal drug delivery has made significant contributions to medical practice but has yet to fully realize its potential as an alternative to oral administration and injections. First-generation systems, which rely on the skin's natural permeability, have been widely used for small, lipophilic drugs. Second-generation systems use chemical enhancers, iontophoresis, and non-cavitational ultrasound to improve delivery, while third-generation systems target the stratum corneum using microneedles, thermal ablation, and electroporation, enabling delivery of macromolecules and vaccines. Transdermal delivery is attractive due to its non-invasive nature, long-term release capability, and improved patient compliance. It has been used for drugs like estradiol, fentanyl, and testosterone, and for vaccines. Over the past few decades, the number of transdermal delivery systems has increased significantly, with more than one billion patches produced annually. Transdermal delivery offers advantages over oral and injectable routes, including avoiding first-pass metabolism and reducing pain and infection risks. However, it is limited to drugs with specific molecular properties. Recent advancements in chemical enhancers, iontophoresis, and physical methods have expanded the range of deliverable drugs, including hydrophilic compounds and vaccines. Third-generation systems, such as microneedles and thermal ablation, have shown promise in delivering macromolecules and vaccines. These methods target the stratum corneum, enhancing permeability without damaging deeper tissues. Clinical trials have demonstrated the safety and efficacy of these approaches, with microneedles showing particular potential for vaccine delivery. Future developments in transdermal delivery aim to improve drug delivery efficiency, safety, and cost-effectiveness. Advances in chemical enhancers, iontophoresis, and physical methods are expected to further expand the range of deliverable drugs and improve patient outcomes. The field is poised to have a significant impact on medicine through continued innovation and clinical application.