Cell-penetrating peptides are short, often hydrophilic peptides that get access to the intracellular milieu. They have aroused great interest both in academic and applied research. First, cellular internalization of CPPs often involves the crossing of a biological membrane (plasma or vesicular), thus challenging the view of the non-permeability of these structures to large hydrophilic molecules. Secondly, CPPs can drive the internalization of hydrophilic cargoes into cells, a rate-limiting step in the development of many therapeutic substances. Interestingly, the two most used CPPs, TAT and penetratin peptides, are derived from natural proteins, HIV Tat and Antennapedia homeoprotein, respectively. The identification of the penetratin peptide, summarized in this review, is intimately linked to the study of its parental natural protein.