Diffuse large B-cell lymphoma is the most common adult non-Hodgkin lymphoma and is potentially curable. Immunochemotherapy, R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone) is the standard of care. This regimen has been incorporated in other approaches and reevaluated in different trials in different age groups. The duration of cycle therapy has varied from 14 to 21 days. In addition, R-ACVBP has been evaluated in randomized trials. Autologous stem cell transplantation (ASCT) has been evaluated in randomized clinical trials. Ongoing studies are evaluating new regimens such as EPOCH-R and novel maintenance therapy approaches in the upfront management of DLBCL. In the relapse and refractory setting, autologous stem cell transplantation remains the standard of care with treatment with R-ICE or R-DHAP followed by different conditioning regimens prior to ASCT. The outcomes of patients who relapse following ASCT are improving with the treatment of new agents targeting different pathways such as lenalidomide. New monoclonal antibodies are under evaluation. The Bruton s tyrosine kinase inhibitor is in early stages of development. Targeted therapy has changed the natural history of diffuse large B-cell lymphoma. Past microarray and new DLBCL hypersequencing data are revealing new pathways and targets to further explore therapeutically. This review will describe the contribution of immunochemotherapy and other interventions in diffuse large B-cell lymphoma evaluating past clinical trials, review early clinical trial observations, and discuss current future directions.