RNA interference (RNAi) is a specific gene-silencing mechanism triggered by small interfering RNA (siRNA). The application of RNAi in the clinic requires the development of safe and effective delivery systems. Efforts have been dedicated to the development of lipid-based systems in siRNA deliveries. Many of the lipid-based delivery vehicles' self-assemble with siRNA are through electrostatic interactions with charged amines. Electrostatic interactions must be stable enough to sustain the nucleic payload in the carrier en route, but must allow dissociation, to execute therapeutic activity, at the delivery site. Internalization of lipid-based siRNA delivery systems into cells typically occurs through endocytosis; accordingly, delivery requires materials that can facilitate endosomal escape. The size of the carrier is important as carriers <100 nm in diameter have been reported to have higher accumulation levels in tumours, hepatocytes and inflamed tissue. To reduce RES uptake and increase circulation time, carriers have been modified on the surface with polyethyleneglycol. Herein, we review basic requirements for building lipid-based siRNA delivery systems.