Diffuse large B-cell lymphoma (DLBCL) accounts for approximately one-third of all non-Hodgkin lymphomas (NHL) and is the most common aggressive NHL. It can arise de novo or as a transformation of an indolent lymphoma. Although rituximab-based immunochemotherapy has improved overall survival (OS) in DLBCL, high-intermediate or high-risk disease is associated with a 4-year OS of approximately 50-60%. Stem cell transplant (SCT) has been extensively investigated in DLBCL in both upfront and salvage settings. Several trials have failed to show an OS benefit with upfront autologous SCT in DLBCL or other aggressive NHL. Therefore, upfront SCT is not currently indicated in an unselected population of patients with aggressive NHL. Approximately 10-15% of patients with DLBCL are refractory to primary rituximab-based therapy or progress soon afterwards. An additional one-third of patients relapse within 2-3 years after initial therapy. Outcomes are generally poor in these patients with chemotherapy alone. Patients, who have chemosensitive relapse are generally taken to autologous SCT if they are transplant candidates. Several strategies including the use of radioimmunotherapy and rituximab have been investigated to improve the outcomes of autologous SCT; however, there is no conclusive evidence of their benefits. Conversely, radiotherapy may have a role and should be utilized before or after SCT in patients with bulky or residual disease in non-irradiated areas. Patients with DLBCL who fail multiple chemotherapies or autologous SCT have poor outcomes with a median OS of approximately 10 months in the rituximab era; such patients should be considered for allogeneic SCT or novel clinical trials. Outcomes with allogeneic SCT are better in patients with good performance status, young age, chemosensitive disease and those who relapse >12 months after autologous SCT. Reduced intensity conditioning or nonmyeloablative conditioning may reduce non-relapse mortality associated with allogeneic SCT, possibly expanding its utilization to older patients. Haploidentical transplant and cord blood transplant are emerging techniques that allow alternative donor options. Advances in the field of autologous and allogeneic SCT continue to change the landscape of hematologic malignancies such as DLBCL.