Second-line therapy options for patients with diffuse large B-cell lymphoma (DLBCL) that is refractory to, or relapses after, current rituximab-containing primary therapy continue to evolve. For younger patients, salvage therapy followed by intensive therapy and autologous stem cell transplant (ASCT) remains the treatment of choice for those with chemotherapy-sensitive disease. Combination therapy may be used for those who are not candidates for ASCT. In contrast, patients with DLBCL refractory to 2 lines of therapy have a very poor prognosis and generally short survival, and should be carefully considered for participation in clinical trials of novel approaches.