Therapeutic proteins have increased dramatically in both number and frequency of use in recent years, primarily owing to advances in protein engineering. Protein therapy provides the advantages of high potency and specificity, as well as low oncogenic risks. To date, due to their inability to cross the plasma membrane into the intracellular space of mammalian cells, most therapeutic proteins can only target secreted modulators or extracellular receptors. The full potential of protein therapy is, however, being gradually realized by the development of various strategies capable of intracellular protein delivery. Notwithstanding, most of these strategies suffer from severe endosomal trapping, resulting in very low protein delivery efficiency. In this Perspective, we discuss various methods to directly transport proteins into the cell cytoplasm, thus bypassing the problems associated with endocytosis.