Since the first Transdermal Therapeutic Systems (TTS) were introduced in the US market two decades ago, more than dozen drugs have been clinically available as skin patches for treating a variety of diseases. These patches are classified into four categories with respect to the formulation designs: (1) the use of high potent drugs, (2) the use of chemical enhancers, (3) the use of an invasive outside energy such as the electric field and ultrasound, and (4) the use of various penetration enhancing technologies combined. In this paper, the advances in TTS are outlined according to the four categories. Some important issues, overlooked for carrying out animal experiments and clinical trials, are also demonstrated.