Diffuse large B cell lymphoma (DLBCL) is the most prevalent non-Hodgkin lymphoma (NHL) in adulthood, comprising 30%–40% of all new diagnoses. This aggressive disease can arise de novo or, less frequently, from the clinical evolution of various indolent B cell malignancies. While durable remissions can be achieved in a substantial proportion of cases by combined chemoimmunotherapy, over 30% of patients will not respond to currently available regimens or will relapse with resistant disease.One explanation for such incomplete therapeutic success is the considerable heterogeneity of this tumor. DLBCL comprises multiple molecular subgroups, which can be recognized by their gene expression profiles and reflect either the stage in B cell development from which the disease originates or the activity of different biological programs, including metabolic dysregulation. DLBCL subgroups differ in the oncogenic pathways that drive them and in their response to treatment. Thus, the recognition of dysregu-lated genes/programs that are critical to the survival of the lymphoma cells is central to the development of rationally targeted therapeutic approaches for DLBCL.