The design of vaccines involving biodegradable polymers as adjuvants provides numerous advantages over traditional administrations. The polymer chemistry can be tailored to optimize the vaccine properties by providing controlled and sustained release of antigen, enhanced stability of immunogenic proteins and the modulation of the immune response. Current adjuvants approved by the FDA enhance humoral immunity response as opposed to cell-mediated immunity, which is needed for diseases that involve intracellular pathogens. Nevertheless, the mechanisms by which adjuvants modulate these specific immune response pathways and establish long term immunologic memory are poorly understood. Our overall objectives are to design novel vaccine adjuvants based on biodegradable polymers and to understand the cellular and molecular mechanisms that establish immunologic memory. The novel amphiphilic polyanhydride system based on the anhydride monomers 1,6-bis(p-carboxyphenoxy)hexane (CPH) and 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) provides a favorable and biocompatible environment for protein stabilization and release, which are essential characteristics for protein/antigen carriers. In vitro and in vivo studies of the adjuvant and immunomodulatory capabilities of the CPTEG:CPH system has been assessed. The in vitro evaluation of bone marrow-derived dendritic cells activation after incubation with CPTEG:CPH microspheres demonstrated an enhancement of surface expression of co-stimulatory molecules and cytokines production. Cell-mediated pathway-inducing cytokines were identified, suggesting that the CPTEG:CPH system biases this pathway. In other studies, the in vivo enhancement and modulation of immune response was evaluated with ovalbumin-loaded CPTEG:CPH microspheres. The formulations of CPTEG:CPH microspheres enhanced T cell proliferation, cytokine production and antibody responses to ovalbumin. Altogether, these studies demonstrated that the novel CPTEG:CPH system is a promising candidate for the development of vaccine-based therapies.