The addition of rituximab to systemic chemotherapy has improved the response rates, progression-free survival, and overall survival of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) compared to chemotherapy alone. In the front-line setting, the use of rituximab is changing the biology and clinical behavior in DLBCL patients who fail to respond or relapse following chemoimmunotherapy. Based on retrospective studies, it is becoming evident that the subset of patients with rituximab/chemotherapy-relapsed/refractory DLBCL represents a different clinical entity with a higher degree of chemotherapy resistance compared to DLBCL patients receiving upfront chemotherapy alone. The backbone of treatment for "sensitive"patients with relapsed/refractory disease continues to be salvage chemotherapy with or without rituximab, followed by high-dose chemotherapy and autologous stem cell support. Patients who are not eligible for high-dose chemotherapy may benefit from a growing number of regimens integrating novel agents with promising activity and manageable toxicity. Advances in biotechnology have led to the development of novel biomarkers used for categorization or risk stratification in DLBCL patients. This two-part review summarizes treatment options for patients with relapsed/refractory DLBCL and stresses the emerging therapeutic challenges for patients who were previously exposed to rituximab.