At the International Workshop on Non-Hodgkin Lymphoma (iwNHL) 2015 meeting, Michael Pfreundschuh, MD, of Universitaetsklinikum des Saarlandes, Homburg, Germany, chairs a discussion with Randy Gascoyne, MD, of the BC Cancer Research Centre, Vancouver, British Columbia, Canada, and Kieron M. Dunleavy, MD, National Cancer Institute, Bethesda, MD. They summarise the biological understanding of the molecular subtypes of diffuse large B-cell lymphoma (DLBCL), including germinal-center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL), with an emphasis on diagnostic and rational therapeutic approaches for the management of these patients.