Vaccination is one of the most successful medical interventions for the prevention of disease in the twentieth century. However, with the development of new and less reactogenic vaccine antigens, which take advantage of molecular recombinant technologies, comes the need for more effective adjuvants that will facilitate the induction of adaptive immune responses. In this context, immunomodulatory biomaterials, particularly the ones based on biodegradable polymers, show great promise. This article discusses the various classes of immunomodulatory biomaterials and advocates a cross-disciplinary approach that brings together molecular concepts from various fields to rationally design vaccine adjuvants with immunomodulatory properties.