PURPOSE OF REVIEW: This review focuses on the findings of recent randomized prospective trials evaluating new therapeutic options for primary central nervous system lymphoma (PCNSL) in first-line treatment and on the most promising novel agents. RECENT FINDINGS: The current standard treatment of newly diagnosed PCNSL has long been depending on high-dose methotrexate (HD-MTX)-based polychemotherapy followed by whole-brain radiotherapy (WBRT). Recent randomized trials have provided evidence that high-dose chemotherapy with autologous stem cell transplantation (ASCT) is a valuable alternative option to WBRT as consolidation after induction HD-MTX-based chemotherapy. For the elderly, cumulative studies confirm that chemotherapy alone as initial treatment is the best approach in this frail population in order to reduce chemoradiation neurotoxicity. If the role of rituximab needs to be further investigated, novel agents such as imids and ibrutinib have shown to be promising drugs to be incorporated in innovative combination treatment. The role of WBRT, at least at conventional dose, is declining in first-line treatment in favor of intensive consolidation chemotherapy with or without ASCT and possibly maintenance chemotherapy in the elderly. Despite their rarity, it has been shown that ambitious randomized trials in PCNSL are feasible thanks to collaborative networks. Summary: The role of WBRT, at least at conventional dose, is declining in first-line treatment in favor of intensive consolidation chemotherapy with or without ASCT and possibly maintenance chemotherapy in the elderly. Despite their rarity, it has been shown that ambitious randomized trials in PCNSL are feasible thanks to collaborative networks.