Since the approval of first transdermal patch (Transderm Scop(®)) containing scopolamine in 1979, the improvement in systemic drug delivery through skin remains incremental. The traditional methods based on passive diffusion of drug molecules in to the skin are unable to deliver macromolecules, such as peptides, proteins, DNA and vaccines, due to the barrier properties of stratum corneum (SC). During the course of approximately 35 years, the focuses are not only to overcome the above barrier property of the skin but also the safety, accuracy and patient compliance aspect of the traditional methods. The former limitation can be overcome by altering the SC barrier function by different active methods such electrically assisted methods (sonophoresis, iontophoresis, electroporation, magnetophoresis, pressure waves, electron beam irradiation), SC abruption (microneedles, high-velocity jet) and SC removal (tape-stripping, suction, microdermabrasion, ablation). This review summarizes basic principles, mechanisms, advantages, limitations and recent development of above physical techniques along with skin anatomy and drug transport pathways across skin.