We have characterized the impact of strain-based genetic differences on the efficiency of the intravenous cationic liposome-DNA complex (CLDC)-based gene transfer and expression in mice. We also investigated what steps in the gene delivery and expression pathway appeared responsible for these strain-related differences and whether such differences could be compensated for either by agents that alter host pathways important in CLDC-mediated gene transfer and expression, or by changes in CLDC formulation. We found that different mouse strains can exhibit different expression levels and/or differences in the amount of plasmid DNA delivered to the organs where the DNA is expressed. Furthermore, drug pretreatment or reformulation of the CLDC could improve DNA delivery and/or gene expression in a strain-specific fashion. We conclude that genetic factors critically modify both the tissue deposition and the expression of genetic materials delivered by CLDC. Because manipulation of either the host or the CLDC could at least partially compensate for these strain-related differences, such strategies may be required to effectively use non-viral gene transfer approaches in genetically diverse populations.