Primary mediastinal large B-cell lymphoma (PMBCL) is a relatively uncommon subtype of non-Hodgkin lymphoma that is distinct from diffuse large B-cell lymphoma (DLBCL). It is generally thought to arise from thymic medullary B-cells. PMBCL is characterized by a pathologic and molecular profile that is between that of DLBCL and nodular sclerosis classical Hodgkin lymphoma. It is a clinically aggressive lymphoma and most frequently occurs in adolescents and young adults, with a slight female predominance. The typical presentation involves an isolated large mediastinal mass with initial locoregional spread to the supraclavicular, cervical, and hilar lymph nodes as well as into the mediastinum and lung, but distant disease can occur in approximately one-quarter of patients at diagnosis. Because PMBCL is relatively uncommon, prospective data to guide treatment remain limited. Therefore, some uncertainty exists regarding the optimal treatment approach. Chemoimmunotherapy with rituximab-containing regimens are recommended and have produced generally favorable results.