Primary mediastinal B-cell lymphoma is a discrete clinicopathologic entity. Molecular analysis reveals it to be distinct from other types of large B-cell lymphoma, and retrospective analysis suggests that it may respond better to multi-agent chemotherapy regimens than to the more commonly used CHOP. The addition of rituximab may mitigate such differences, and may also diminish the role of consolidation radiotherapy, which is often used to treat residual mediastinal masses. For the future the role of FDG-PET scanning requires prospective examination, and it is hoped that this may allow the de-escalation of treatment if it can be shown to yield reliable prognostic information. The relative rarity of this type of lymphoma necessitates international collaboration in clinical trials, with a prospective clinicopathologic study, IELSG 26, already underway.