DNA transfection and gene expression are very complex processes. To date not many studies have dealt with the mechanisms involved. Only some particular steps were studied. Early models, based on rhodamine lipid fluorescence studies which quickly spread to the cell surface, envisioned complex fusion with cell membranes (Feigner et al., 1987), while recently most researchers believe that the complex enters cells by an endocytotic pathway (Zabner et al., 1995; Farhood and Huang, 1996; Friend et al., 1996). In addition, the possibility of decondensation of DNA upon its release from the endosome by anionic lipids from the outer endosome surface was demonstrated (Xu and Szoka, 1996). Anionic (PS/PE/PC 1/2/1) liposomes were shown to rapidly release DNA complexed to DOTAP liposomes at neutral charge ratios. DNA was also released upon incubation with heparin and dextran sulfate while DNA, RNA, poly(glutamic acid), spermidine, spermine, and histones did not induce DNA release. These results suggest that DNA may become decondensed upon release from the endosomes in which the cytosol-facing membrane has similar lipid composition (Xu and Szoka, 1996). Obviously, some still unknown membrane disruption must occur in order that the two systems can interact.