Primary mediastinal B-cell lymphoma (PMBCL) is a recognised subtype of diffuse large B-cell lymphoma according to the WHO classification that represents approximately 5% of aggressive lymphomas, and 2% of all cases of lymphomas. It presents with unique clinical, morphologic and immunophenotypic characteristics that define the disease. Retrospective studies have found that PMBCL patients have excellent survival rates with a distinct plateau and a trend to better outcome if treated with dose-intensified chemotherapy with MACOPB or VACOPB. In spite of the multiple molecular data known, generated on the pathogenesis of this tumour, treatment is still essentially based on a combination of chemo and immunotherapy. We take this opportunity for reviewing the recent biologic data provided by gene expression profiling of the tumour, for discussing new potential therapeutic targets.