John Gribben, MD, DSc, FRCP, FRCPath, FMed Sci, Barts Cancer Institute, London, UK, Laurie Sehn, MD, BC Cancer Agency, Prince George, BC, Canada, and David Maloney, MD, PhD, Fred Hutchinson Cancer Research Centre, Seattle, WA, discuss the challenge of targeting lymphoma despite the molecular complexity leading to various subgroups of disease, at the 17th International Workshop on Non-Hodgkin Lymphoma, Boston, MA. They debate whether the classic approach to clinical trial design might need improvement, mainly focusing on patient selection, highlighting how evidence suggests there are five subtypes of diffuse large B-cell lymphoma. They suggest that using patient outcome to later understand molecular pathology might be the way forward.