Diffuse large B-cell lymphoma (DLBCL) remains a curable lymphoma, with improved outcome resulting in large part from the incorporation of rituximab in standard regimens. The disease is heterogeneous clinically, morphologically, and molecularly. Recent insights into the molecular heterogeneity of DLBCL are beginning to yield novel therapeutics with significant promise for key subsets of patients. Although cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone chemotherapy with rituximab remains a standard therapeutic approach for most patients who have DLBCL, it is anticipated that novel agents will be included in treatment regimens for many patients in the near future.