The cell membrane represents a major barrier for efficient delivery of exogenous molecules, either pharmaceuticals or genetic material, under both in vitro and in vivo conditions. The number of methods employed to attempt safe, efficient, and local drug and gene delivery has increased during the recent years. One method for membrane permeabilization, electroporation, has already been translated to clinical practice for localized anticancer drug delivery and is termed "electrochemotherapy". Clinical trials for gene delivery using electroporation as well as drug delivery using another cell permeabilization method, sonoporation, are also underway. This review focuses on these two methods, including their fundamental principles and state-of-the-art applications. Other techniques, such as microinjection, magnetoporation, photoporation, electrospray, and hydrodynamic and ballistic gene delivery, are also discussed.