Primary mediastinal large B-cell lymphoma represents a distinct entity with unique clinicopathologic features and a molecular gene-expression signature reminiscent of nodular sclerosis subtype of classical Hodgkin's lymphoma. Recent studies, including those using a refined molecular signature, suggest that the outcome is more favorable than that of diffuse large B-cell lymphoma. Using historical comparisons, dose-dense and dose-intensive regimens may be more effective than cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy; however, the impact of adding rituximab to these regimens and effect on outcome comparisons is unknown. Clinical trials exploring these questions in addition to the benefit of consolidative radiotherapy are necessary to definitively answer these questions.