Diffuse large B cell lymphoma (DLBCL) in the most common type of non-Hodgkin’s lymphoma (NHL) in developed world, so far and approximately 60,000 new non-Hodgkin lymphoma (NHL) cases and 20,000 deaths have been estimated in the United States for 2010. In spite of novel therapeutic options have been suggested and successfully tried in patients with lymphoproliferative disorders, the standard first- line treatment for DLBCL has remained the same combination of chemotherapy and CD20 (activated-glycosylated phosphoprotein) targeting monoclonal antibody rituximab (R) with 30% to 40% chance of relapse after first line R-CHOP treatment. Diffuse large B-cell Lymphoma is a distinct histological type within mature B-cell NHL that is characterized by large tumor cells and aggressive clinical behavior. Several clinical trials have been designed to evaluate safety, efficacy and superior clinical benefit by adding novel agents, intensifying cycles of treatment or substituting rituximab with new CD20 targeting immunotherapies. Intensification of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) chemotherapy from 3-week interval cycles to 2-week interval cycles has already shown clinical benefit in a German trial but failed to show improved overall and disease free (DFS) survival in both elderly (60 to 80 years) and young patients in randomized phase 3 clinical trials. In the GELA study of R-CHOP versus CHOP front line therapy in elderly subjects, following R-CHOP treatment the 5-year event-free survival (EFS) was 47%, the 5-year progression free survival (PFS ) was 54%, and the 5-year overall survival (OS) was 58%3. Namely, in a phase 2 randomized clinical trial (PYRAMID) as a first line treatment for non-Germinal Center Cell (GCB) subtype of DLBCL the results were in favor of R-CHOP and adding bortezomib was not found to improve DFS and OS significantly. Immunomodulatory agent lenalidomide is another attractive therapeutic option for non-GCB subtype of DLBCL. Statistically significant difference between non-GCB and GCB controls treated with standard R-CHOP alone in terms of progression-free survival (28% vs. 64%; P = .00029) and overall survival (46% vs. 74%; P = .000036) was reported while non-GCB and GCB treated with R-CHOP plus lenalidomide had similar rates of progression (60% vs. 59%; P = 0.83) and overall survival at 2 years (83% vs. 75%; P = .61). Despite these promising clinical results, further clinical studies, especially phase 3 randomized clinical trials are required to confirm the alternate competitive treatment for DLBCL patients. arious strategies have been implemented to improve the outcomes of diffuse large B-cell lymphoma (DLBCL. As such, molecular classification of DLBCL is not only important for prognostication, but moves to center stage for personalization of therapy for DLBC.). In recent years, remarkable advances have been achieved, based on the discovery of cell-of-origin in DLBCL and on more effective targeted agents. A number of early clinical trials evaluating combinations of novel targeted agents with standard chemotherapy (R-CHOP) have been completed and have demonstrated the feasibility of this approach with encouraging efficacy.