Polymer microspheres have shown great potential as a next generation adjuvant to replace or complement existing aluminum salts for vaccine potentiation. Microsphere-based systems can now be made to deliver subunit protein and peptide antigens in their native form in a continuous or pulsatile fashion for periods of weeks to months with reliable and reproducible kinetics, often obviating the need for booster immunizations in animal models. Microspheres have also shown potential as carriers for oral vaccine delivery due to their protective effects on encapsulated antigens and their ability to be taken up by the Peyer's patches in the intestine. The potency of these optimal depot formulations for antigen may be enhanced by the co-delivery of vaccine adjuvants, including cytokines, that are either entrapped in the polymer matrix or, alternatively, incorporated into the backbone of the polymer itself and released concomitantly with antigen as the polymer degrades. In this article we review the use of polymer microspheres for single-step immunization and discuss future applications for the improvement of vaccines and immunotherapies by utilizing encapsulation technology.