The management of diffuse large B-cell lymphoma (DLBCL) has been gradually evolving since the discovery of its 2 major forms, the germinal center B-like (GCB) and activated B-cell (ABC) types. Although the reference standard for the identification of these cell types is considered gene expression profiling (GEP), currently the only method commercially available is immunohistochemistry (IHC). The application of various IHC-based algorithms and their correlation with GEP and clinical outcome are discussed. Because of the adverse prognostic implications of the non-GCB type and its potential effects on treatment selection, the recently revised World Health Organization classification has included these biologic cell types. The management of double hit lymphomas, which almost exclusively fall under the GCB category, is discussed, together with the double expresser phenotype, which is usually grouped under the non-GCB type. The role of lenalidomide and ibrutinib in the management of the non-GCB type is examined. We also discuss the front-line management of primary mediastinal large cell lymphoma using the EPOCH (etoposide, prednisolone, Oncovin [vincristine], cyclophosphamide, hydroxydaunorubicin [doxorubicin]) regimen and examine new salvage data on immune checkpoint inhibitors for this clinical subtype. The prognosis, clinical features, and management of de novo CD5+ DLBCL are discussed, and newer and promising developments in the management of primary central nervous system lymphomas are presented in detail. The most popular salvage regimens and the application of high-dose chemotherapy with stem cell transplantation are assessed in detail. Finally, data on new treatment tactics such as CART (chimeric antigen receptor T-cell) cells and promising new drugs, including blinatumomab and venetoclax, are presented.