Recent advances in diffuse large B-cell lymphoma are changing the way pathologists approach, diagnose, and report on this heterogeneous group of lymphomas. The purpose of this review is to provide a practical yet comprehensive approach to diffuse large B-cell lymphoma and aggressive B-cell lymphomas that can be used and easily interpreted by pathologists at all levels of training. It will address important concepts and current testing modalities which provide important prognostic information for the clinician when considering appropriate chemotherapeutic regimens for each patient's lymphoma diagnosis. It will also provide some insights into recently reported signaling pathways and molecular alterations and their contribution to lymphomagenesis and how identifying these abnormalities may provide future potential therapeutic targets for these aggressive lymphomas.