Nucleic acid transfer in mammalian cels is drastically improved with devices which increase their delivery in the cytosol upon endocytosis. In this chapter, we describe the effect on plasmid DNA (pDNA) and oligonucleotide (ODN) transfer, of an histidine-rich peptide (H5WYG), histidylated oligolysine (HoK), and histidylated polylysine (HpK) designed on the basis of the membrane destabilization capacity of poly-L-histidine at a pH dose to that of the endosomes. We report that H5WYG, which permeabilizes the cell membrane at pH 6.4, favors the transfection mediated by lactosylated polylysine/pDNA complexes and, by lowering the pH of extracellular medium, allows the loading of the cytosol and the cell nucleus with ODN. We show that HoK forms small cationic spherical particles of 35 nm with ODN and HpK rod or toroid cationic particles of 100 nm with pDNA. PEGylation stabilizes these particles at physiological salt concentration. We also show that (i) HoK/ODN complexes yield a more than 20-fold increase of the biological activity of antisense ODN towards the inhibition of transient as well as constitutive gene expression and (ii) HpK/pDNA complexes yield a transfection efficiency of 3-4.5 order of magnitude higher than do polylysine/pDNA complexes. We also provide evidence that the effect of these polyhistidylated molecules is mediated by imidazole protonation in endosomes. Overall our data show that polyhistidylated molecules constitute interesting devices for an efficient cytosolic delivery of nucleic acids, and that ionic complexes between histidylated polylysine and a pDNA are attractive for developing a nonviral gene delivery system.