A key hurdle for the further development of RNA interference (RNAi) therapeutics like small interfering RNA (siRNA) is their safe and effective delivery. Lipids are promising and versatile carriers because they are based on Nature's own building blocks and can be provided with properties which allow for protection of the siRNA, steric stabilization, targeting, membrane fusion and triggered drug release. At present a variety of lipid-based transfectants for siRNA delivery have been used for in vitro and in vivo purposes. The majority bears a cationic charge to electrostatically complex the siRNA into more hydrophobic lipoplexes, which promote passage of the siRNA across cellular membrane barriers, especially when lipids are added that facilitate membrane fusion. Despite these attractive features, siRNA delivery vehicles are facing a number of challenges such as the limited delivery efficiency in vivo, toxicity and non-specific stimulation of the immune system. To optimally design and tailor the lipidic systems for siRNA delivery, better insight is needed into the mechanisms of cell delivery. More specifically, further clarification is need regarding the nature of cell surface interactions, routes of internalization, passage of intracellular membranes, and mechanisms of immune activation. This review provides an overview of the main constituents currently employed in lipid-based siRNA carriers, and recent research into improvements of cell delivery. In addition, pitfalls related to immune activation and side effects are discussed, and possible ways to overcome them are highlighted.