Large B-cell lymphomas, with an estimated 150,000 new cases annually worldwide, represent almost 30% of all cases of non-Hodgkin’s lymphoma. Patients typically present with progressive lymphadenopathy, extranodal disease, or both and require therapy. Despite the advanced stage at presentation in the majority of patients, more than 60% can be cured with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy (Fig. 1A). Patients with treatment failure after R-CHOP often have a poor outcome — in particular, those with disease that is refractory to frontline or subsequent therapies — although some patients can have a durable remission and be cured after secondary therapies. Over the past two decades, improved insights into large B-cell lymphomas, in terms of epidemiology, prognostic factors, and biologic heterogeneity, have led to a refinement of disease classification and the development of new therapeutic approaches.