Transdermal drug delivery has significantly contributed to medical practice but has not yet fully realized its potential as an alternative to oral and intravenous administration. First-generation systems, which have been widely used for small, lipophilic, low-dose drugs, have been complemented by second-generation systems using chemical enhancers, iontophoresis, and non-cavitational ultrasound, which have led to the development of clinical products. Third-generation systems, which target the stratum corneum barrier using microneedles, thermal ablation, microdermabrasion, electroporation, and cavitation ultrasound, are now being tested for delivering macromolecules and vaccines. These advancements have positioned transdermal drug delivery to have a significant impact on medicine, offering advantages over oral and intravenous routes, such as reduced first-pass metabolism, pain, and the risk of disease transmission. However, the field faces challenges in delivering hydrophilic drugs and macromolecules, and the safety of invasive methods like microneedles and thermal ablation remains a concern. Despite these challenges, the future of transdermal drug delivery looks promising, with ongoing clinical trials and the development of novel enhancement strategies.Transdermal drug delivery has significantly contributed to medical practice but has not yet fully realized its potential as an alternative to oral and intravenous administration. First-generation systems, which have been widely used for small, lipophilic, low-dose drugs, have been complemented by second-generation systems using chemical enhancers, iontophoresis, and non-cavitational ultrasound, which have led to the development of clinical products. Third-generation systems, which target the stratum corneum barrier using microneedles, thermal ablation, microdermabrasion, electroporation, and cavitation ultrasound, are now being tested for delivering macromolecules and vaccines. These advancements have positioned transdermal drug delivery to have a significant impact on medicine, offering advantages over oral and intravenous routes, such as reduced first-pass metabolism, pain, and the risk of disease transmission. However, the field faces challenges in delivering hydrophilic drugs and macromolecules, and the safety of invasive methods like microneedles and thermal ablation remains a concern. Despite these challenges, the future of transdermal drug delivery looks promising, with ongoing clinical trials and the development of novel enhancement strategies.