High-dose methotrexate (HD-MTX)-based chemotherapy is the current first-line therapy for primary CNS lymphoma. Whole-brain radiotherapy (WBRT) plays an important role in the management of primary CNS lymphoma and is indicated in patients with contraindication to chemotherapy, in patients with unusual histologic subtypes as curative treatment, as complementary therapy for patients failing to achieve complete remission after systemic chemotherapy and as salvage therapy for refractory or relapsing patients when systemic chemotherapy is no longer advisable. The two major pitfalls in WBRT use are transitory efficacy and neurotoxicity with deterioration of quality of life. Accordingly, WBRT administration as consolidation therapy in complete remission patients after first-line chemotherapy is controversial. In the present review, indications of WBRT will be outlined with emphasis on consolidation therapy, treatment-related neurotoxicity and efforts aimed at reducing toxicity.