Diffuse large B cell lymphoma (DLBCL), the most common subtype of aggressive lymphoma, has considerable biologic and clinical heterogeneity. Despite recent therapeutic advances, up to 50% of patients relapse after standard chemoimmunotherapy. The International Prognostic Index (IPI) at relapse is of value in providing prognostic information on response to salvage chemotherapy and outcome after autologous hematopoietic cell transplantation (aHCT). Predictive biologic and gene expression markers, however, remain undefined, and require further clarification from additional molecular studies. To date, the standard of care in the management of relapsed/refractory DLBCL is salvage chemotherapy followed by an aHCT for those with chemotherapy-sensitive disease. Currently, there is no standard salvage chemotherapy regimen, and the use of immunotherapy for relapsed disease requires further evaluation. This review focuses on prognostic markers, current salvage therapies, and discusses the role of novel treatment in the management of relapsed/refractory DLBCL.