Disease Overview Diffuse large B‐cell lymphoma (DLBCL) is the most common type of aggressive non‐Hodgkin lymphoma originating from the germinal center, and it represents a heterogeneous group of diseases with variable outcomes that are differentially characterized by clinical features, cell of origin (COO), molecular features, and most recently, frequently recurring mutations. Diagnosis DLBCL is ideally diagnosed from an excisional biopsy of a suspicious lymph node, which shows sheets of large cells that disrupt the underlying structural integrity of the follicle center and stain positive for pan‐B‐cell antigens, such as CD20 and CD79a. COO is determined by immunohistochemical stains, while molecular features such as double‐hit or triple‐hit disease are determined by fluorescent in situ hybridization analysis. Commercial tests for frequently recurring mutations are currently not routinely used to inform treatment. Risk Stratification Clinical prognostic systems for DLBCL, including the rituximab International Prognostic Index, age‐adjusted IPI, and NCCN‐IPI, use clinical factors for the risk stratification of patients, although this does not affect the treatment approach. Furthermore, DLBCL patients with non‐germinal center B‐cell (GCB)‐like DLBCL (activated B‐cell like and unclassifiable) have a poorer response to up‐front chemoimmunotherapy (CI) compared to patients with GCB‐like DLBCL. Those with c‐MYC‐altered disease alone and in combination with translocations in BCL2 and/or BCL6 (particularly when the MYC translocation partner is immunoglobulin) respond poorly to up‐front CI and salvage autologous stem cell transplant at relapse. Risk‐Adapted Therapy This review will focus on differential treatment of DLBCL up‐front and at the time of relapse by COO and molecular features.