For almost 30 years, studies have confirmed the effectiveness of cell-penetrating peptides (CPPs) in the facilitation of the intracellular delivery of various cargo molecules, including RNA, DNA, plasmids, proteins or nanoparticles, under in vitro and in vivo conditions. The cellular uptake of CPPs occurs via energy-dependent, as well as -independent mechanisms. In this relatively new direction of research, studies have attempted to introduce genome modification systems into cells by CPPs. Cellular uptake of CPPs carrying either covalently bound or electrostatically conjugated cargo, has several advantages over viral delivery systems, as it does not lead to any significant cytotoxicity or immunogenicity, and simultaneously it is more efficient than other non-viral systems. So far, CPPs have been successfully used to introduce Cre recombinase, zinc finger nucleases, transcription activator-like effector nucleases and clustered regularly interspaced short palindromic repeats systems into cells. The present article systematically reviewed the information obtained from studies on CPPs and assessed their utility with regard to their effectiveness and safety of use.