The addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy was a milestone in the development of front-line therapy for diffuse large B-cell lymphoma (DLBCL). R-CHOP and equivalent rituximab-containing anthracycline-based regimens are now widely accepted as the standard of care in this setting. However, the optimal treatment for patients with DLBCL relapsing or progressing after front-line therapy is not yet established. This review explores the role of rituximab in the treatment of DLBCL in the salvage setting, as monotherapy, in combination with chemotherapy or novel agents, and in the context of autologous stem cell transplantation (ASCT). Current evidence suggests that rituximab may improve outcomes in several ways: the higher response rates achieved with rituximab-based induction in the salvage setting optimize the number of patients who are able to proceed to high-dose therapy -ASCT; rituximab may improve outcomes following ASCT when used as post-transplantation consolidation/maintenance therapy; and addition of rituximab to salvage regimens may improve outcomes for patients ineligible for transplantation. However, patients refractory to or relapsing after first-line therapy (including rituximab-based regimens) still have a poor prognosis. In conclusion, rituximab in salvage therapy for DLBCL is effective and well tolerated. Ongoing studies will further clarify the optimal use of rituximab in the salvage setting.