Background <p>Transdermal Drug Delivery Systems (TDDS) offer a non-invasive route for sustained systemic or localized drug delivery. By bypassing hepatic first-pass metabolism and improving bioavailability, TDDS enhances patient compliance, especially in the management of chronic diseases. Drug permeation across the skin is mediated through pathways involving the complex skin barrier, predominantly the stratum corneum, with efficacy influenced by both drug properties and skin physiology.</p> Methods <p>This review systematically integrates the fundamental mechanisms underlying TDDS, highlights cutting-edge technological advancements developed to overcome the skin barrier, and discusses their expanding clinical applications. The advanced technologies covered include permeation enhancers, vesicular systems (liposomes, transfersomes, ethosomes), microemulsions, microneedles (MNs), responsive systems (pH-, temperature-, enzyme-sensitive), and 3D printing.</p> Results <p>These innovative technologies effectively enhance drug flux, enable targeted delivery, and achieve spatiotemporal control of drug release. Clinically, FDA-approved TDDS formulations have been successfully applied to manage various conditions, including chronic pain (fentanyl, buprenorphine), neurological disorders (rotigotine, rivastigmine), cardiovascular diseases (nitroglycerin, clonidine), hormone replacement, and substance dependence (nicotine). Despite significant clinical value, TDDS still faces challenges such as limitations in delivering macromolecules, potential skin irritation, and inter-individual variability.</p> Conclusion <p>Future directions in TDDS research focus on integrating nanotechnology, AI-driven optimization, wearable sensors, and closed-loop smart systems. These integrations aim to achieve greater precision, personalization, and efficiency in transdermal drug delivery, providing valuable insights for future research and translational development.</p>