Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive B-cell lymphoma and highly heterogeneous disease. With the standard immunochemotherapy, anti-CD20 antibody rituximab (R-) plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy, 30-40% of DLBCLs are refractory to initial immunochemotherapy or experience relapse post-therapy with poor clinical outcomes despite salvage therapies. Mechanisms underlying chemoresistance and relapse are heterogeneous across DLBCL and within individual patients, representing hurdles for targeted therapies targeting a specific oncogenic signaling pathway. In recent years, paradigm-shifting immunotherapies have shown impressive efficacy in various cancer types regardless of underlying oncogenic mechanisms. Vaccines are being developed for DLBCL to build protective immunity against relapse after first complete remission and to promote antitumor immune responses synergizing with immune checkpoint inhibitors to treat refractory/relapsed patients. This article provides a brief review of current progress in vaccine development in DLBCL and discussion on immunologic mechanisms underlying the therapeutic effectiveness and resistance.