The use of cationic lipid-DNA complexes (lipoplexes) for gene therapy of oral squamous cell carcinoma may be limited by the resistance of some cell types to transfection. Using fluorescence microscopy, fluorometry and luciferase luminescence, the authors examined whether the variability arises from the intracellular fate of lipoplexes. In transfection-resistant cells, the efficacy-limiting step appeared to be lipoplex processing beyond binding and internalization, possibly including DNA escape into the cytoplasm and transport into the nucleus.