Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive non-Hodgkin lymphoma. Combination chemotherapy with immunotherapy can be curative, however, nearly one-third of patients will have a disease that is refractory or will relapse (R/R) after standard first-line therapy. In second-line, the standard treatment strategy for fit patients has been high dose chemotherapy followed by autologous stem cell transplant for a quarter-century, however more than half of patients have chemotherapy-refractory disease with this approach. The patients not cured with current chemotherapy-based approaches may benefit from immunotherapy. Several classes of immunotherapy have been developed including antibody-drug conjugates, bispecific T-cell engaging antibodies, immune checkpoint inhibitors and chimeric antigen receptor T-cells. In the following review, we discuss the currently available immunotherapeutic options for patients with R/R DLBCL.