Cationic liposome-nucleic acid complexes, which were originally developed for use as non-viral gene delivery vectors, may now have an equally important application as immunotherapeutic drugs. Recent studies have highlighted the ability of cationic liposomes to potently activate the innate immune system when used to deliver certain Toll-like receptor (TLR) agonists. The immune-enhancing properties of cationic liposomes have been most clearly demonstrated when combined with nucleic acid agonists for endosomally located TLRs, including TLR3, TLR7/8 and TLR9. Immune potentiation by cationic liposomes likely results from the combined effects of endosomal targeting, protection of nucleic acids from extracellular degradation, and from signaling via newly identified cytoplasmic receptors for nucleic acids. The potent innate immune stimulatory properties of liposome-nucleic acid complexes make them particularly attractive as non-specific immunotherapeutics and as vaccine adjuvants. Liposome-nucleic acid complexes have demonstrated impressive anticancer activity in a number of different animal tumor models. Moreover, liposome-nucleic acid complexes have also been shown to be effective for immunotherapy of acute viral and bacterial infections, as well as chronic fungal infections. When used as vaccine adjuvants, liposome-nucleic acid complexes target antigens for efficient uptake by dendritic cells and are particularly effective in eliciting CD8(+) T-cell responses to protein antigens. Thus, liposome-nucleic acid complexes form a potent and versatile immunotherapeutic platform.