Cationic polymers possess no fusogenic property per se. This is why polylysine and similar fully cationized polymers require chloroquine, a lysosomotropic drug used to unmask the intravacuolar malaria parasite, to become effective transfection agents. However, cationic polymers [31], such as polyamine dendrimers [32,33] or polyethylenimine (PEI) [34], share with chloroquine the ability to buffer the acidity of endosomes. The vacuolar pH should therefore decrease more slowly, with a large concomitant ionic concentration increase. Osmotic swelling due to water entry may then burst the vacuole and release the complex into the cytoplasm. This ‘proton sponge’ hypothesis [34] proved to be fruitful, as it led to the design of other effective cationic polymers [35–37]. It was supported recently by the fact that PEI transfection efficiency is not increased by chloroquine, but tremendously de creased by bafilomycin A, a specific vacuolar H+ - ATPase inhibitor [38]. It was also questioned [39] based on average vacuolar pH measurements, yet the involvement of only a tiny fraction of the complexes into the pathway leading to transfection may have been overlooked.