Compared with some other malignancies, where treatment decisions can be influenced by tumor nucleic acid mutational sequencing or by the presence of a protein biomarker, the current management of diffuse large B-cell lymphoma (DLBCL) is not particularly sophisticated. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has been the standard for the past 20 years. This regimen, administered in six 3-week cycles, can be expected to cure about 65% of patients with advanced-stage disease. Patients with limited-stage disease can often be managed with fewer total cycles of therapy, with optional inclusion of external beam radiation. Approximately 85% of limitedstage patients can be expected to be cured. There are some nuances to management. Elderly/frail patients may need a dose-attenuated regimen, such as R-miniCHOP. Patients with poor baseline cardiac function may need a substitution of doxorubicin with etoposide (rituximab, cyclophosphamide, etoposide, vincristine, and prednisone [R-CEOP]). Patients with biologic variants of DLBCL, such as double-hit DLBCL or primary mediastinal DLBCL, may be better served with more intensive regimes such as dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and rituximab (EPOCH-R). Patients at high risk for CNS recurrence have historically received some form of CNS prophylaxis although recent data call this practice into question.