A quarter century has passed since the paradigm for treating aggressive histologies of non-Hodgkin lymphoma (NHL) presenting with limited extent of disease (LD) changed from using aggressive surgical staging techniques followed by primary radiotherapy (RT) to clinical staging followed by initial treatment with doxorubicin-containing chemotherapy (CT). This paradigm shift occurred for two reasons. First, unlike the predictable contiguous spread of Hodgkin lymphoma from one lymph node region to the next, the NHLs are largely systemic diseases characterized by early hematogenous spread. Second, the discovery of a potential curative combination of drugs, including cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), for use in advanced disease could eradicate micro-metastatic disease in patients with LD. The focus of current investigation on controlling the systemic nature of the disease has not changed. In this regard, new effective systemic therapies using combination chemotherapy plus monoclonal antibodies have resulted in improved outcome for patients with advanced disease and those treatment strategies are now under investigation in patients with LD.