A precision approach to DLBCL. Double-hit status should be assessed on all patients and treated accordingly on a clinical trial or using the DA R-EPOCH platform. Assessment of cell of origin, using either immunohistochemistry, gene expression profiling, or in the future the Lymph2Cx assay then should allow patients to be separated into ABC and GCB subtype; there are several phase 3 trials evaluating unique approaches to the former. R-CHOP is adequate therapy for the GCB subtype, which is not double-hit. Primary mediastinal DLBCL is a unique clinicopathologic entity with specific treatment recommendations.