Liposome-mediated nucleic acid delivery has been a focus recently, but in the course of delivering nucleic acid, some hurdles seriously limit the nucleic acid exerting treatment effect. This review refers to a series of problems such as low blood stability, reticuloendothelial system absorption, the lower targeting of liposome and the restriction of endosomal escape which are suffered in liposome-mediated nucleic acid delivery; and gives a detail introduction of strategies such as PEGylation, ligand modification, photochemical internalization, the application of degradation liposome and membrane-lytic peptide, to overcome those problems.