Polyphosphazene polyelectrolytes are synthetic, biodegradable polymers that have shown great potential in vaccine and drug delivery applications. Numerous investigations in laboratory animals have revealed that polyphosphazenes are also potent immunological adjuvants that can dramatically enhance the magnitude, quality and duration of immune responses to a variety of bacterial and viral vaccine antigens. Evidence is accumulating that these polymers have potent adjuvant activity in large animals as well. Interestingly, polyphosphazenes can be combined with novel immune modulatory agents resulting in even more potent immune activity and protection against experimental infection. While most reports are on the activity of polyphosphazenes in aqueous formulations, these polymers can also be easily made into microparticles, making them especially attractive for mucosal delivery. The mechanisms which mediate the adjuvant activity of polyphosphazenes are not fully understood, but there is evidence to suggest that activation of innate immunity may be involved. Further research and development of polyphosphazene adjuvants is warranted to fully explore their potential in the delivery of vaccines and immunotherapeutic agents.