Nanoparticles, microparticles, and other biomaterials are advantageous in vaccination because these materials provide opportunities to modulate specific characteristics of immune responses. This idea of “tuning” immune responses has recently been used to combat infectious diseases and cancer, and to induce tolerance during organ transplants or autoimmune disease. Lymph nodes and other secondary lymphoid organs such as the spleen play crucial roles in determining if and how these responses develop following vaccination or immunotherapy. Thus, by manipulating the local microenvironments within these immunological command centers, the nature of systemic immune response can be controlled. This review provides recent examples that harness the interactions between biomaterials and lymph nodes or other secondary lymphoid organs to generate immunity or promote tolerance. These strategies draw on mechanical properties, surface chemistry, stability, and targeting to alter the interactions of cells, signals, and vaccine components in lymph nodes. While there are still many unanswered questions surrounding how best to design biomaterial-based vaccines to promote specific structures or functions in lymph nodes, features such as controlled release and targeting will help pave the way for the next generation of vaccines and immunotherapies that generate immune responses tuned for specific applications.