Abstract: Cell-penetrating peptides are composed of positively-charged amino acids that can mediate molecules or nano-carriers across cell membranes. However, most of the known cell-penetrating peptides have no cell-or tissue-specificity, with affinity to almost all types of cells in internalization. The non-specificity of cell-penetrating peptides is a significant obstacle in the application to targeted delivery of imaging probes and therapeutic agents. Accordingly, many studies focused on selective switching of systemically-delivered inert cell-penetrating peptides into active forms in diseased tissues. Tsien groups introduced the concept of activatable cell-penetrating peptides in 2004. Subsequently, a growing number of similar delivery systems (molecular or nano-sized) have been documented, and the sensitive factors have included enzyme, lower pH, light and exogenous component. In this paper, we make an overview of the development of activatable delivery system in recent years.