RNAi therapeutics, has quickly been established as a robust and effective gene silencing strategy and has several distinct advantages over traditional pharmaceutical drugs. The reason of the limited number of siRNA delivery systems in clinical trials is certainly the complexity of the approach. It is easier to administer naked or modified siRNA than to develop an efficient, reproducible and safe delivery system which has to undergo the same regulatory guidelines as the drug itself. The nature and extent of these gene expression changes are dependent on several factors including delivery system variables such as its chemistry, lipid architecture, charge, dose, the degree of saturation of cationic lipids affects lipid pKa, fusogenicity, cellular uptake, gene silencing ability and biological variables. Extensive investigations into the chemistry and physics of cationic lipids and their transfection efficiencies points in lipoplex formulation are equally important for transfection.