Rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone immunochemotherapy remains standard of care for first-line treatment of diffuse large B-cell lymphoma (DLBCL). High-dose chemotherapy and stem cell transplantation is offered to most relapsing/refractory patients who respond to salvage therapy. This Q&A review evaluates recommended management strategies for second and subsequent lines of therapy in patients with DLBCL, outlining the relative efficacies of currently available options including novel agents such as ibrutinib and CAR-T cells. The combination of pixantrone and rituximab is currently under investigation as a second-line treatment for patients ineligible for stem cell transplantation, while pixantrone monotherapy is the only therapeutic option approved for multiply relapsed and refractory DLBCL beyond the second line at this time.