Transdermal drug delivery systems (TDDS) offer a non-invasive alternative to oral and injectable routes, providing controlled release and improved patient compliance. Recent advancements in nanotechnology, biomaterials, and physical enhancement techniques have significantly expanded the scope of TDDS for both systemic and localized therapy. This review discusses the evolution of TDDS, focusing on patch technologies, penetration enhancers, and emerging strategies like iontophoresis and sonophoresis. Applications in pain management, hormone therapy, and dermatological conditions are highlighted, alongside challenges and future directions.