The purification of recombinant proteins is a complicated process that requires a thorough understanding of the physical and chemical properties of each protein of interest. The unique characteristics of each protein require the development of a complicated, multi-step process consisting of several orthogonal chromatographic techniques. Although affinity tag methods have been useful in simplifying this process, these approaches have significant drawbacks when tagless proteins are required. Therefore, the development of a flexible, economical, and efficient purification platform for traceless and tagless target proteins would represent a significant advance in bioprocess development. Self-cleaving tags have enabled purification of a broad range of target proteins using simple affinity approaches, but with the ability to ultimately deliver a tagless target protein. Thus these tags potentially offer a purification platform analogous to Protein A, but without the limitation to antibody targets. This review summarizes the advances in developing various intein-based self-cleaving tag technologies, their preferred cleavage conditions (reducing agents, pH, temp, etc.) and the effect of different target proteins on intein catalytic activity. We also discuss engineered inteins whose activity (protein splicing or cleavage) is stringently controlled/triggered by small molecules, light, or environmental condition such as salt concentration. (c) 2017 Society of Chemical Industry