Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in the Western world,and is potentially curable with standard R-CHOP chemoimmunotherapy. We are now in an era that the heterogeneity of DLBCL is defined genetically and molecularly,and rational subset-specific therapeutic targets are guiding clinical trials.Primary mediastinal DLBCL is a unique clinicopathologic entity, and alternatives to R-CHOP may confer superior outcome. Rearrangement of the myc oncogene occurs in 10%of patients with DLBCL, and confers a very poor prognosis with standard R-CHOP, particularly when there is concomitant rearrangement of bcl-2, a condition referred to as double-hit DLBCL. A larger subset of DLBCL demonstrates overexpression of both myc and bcl-2 by immunohistochemistry. Analyze the source of cells by gene expression profile, immunohistochemistry algorithms,or a novel Lymph2Cx platform,provides prognostic information, and guides therapeutic decisions in both relapsed and de novo disease. This article reviews latest research presented at the 57th American Society of Hematology (ASH) annual meeting on the definition of specific subsets of DLBCL and selection of subtype-specific treatment,including novel approaches under investigation. Understanding these key features of the pathology report, and limitations of these assays defining subsets of DLBCL, allows for a precision medicine approach to this disease.