The risk of CNS dissemination and CNS prophylaxis strategies in aggressive non-Hodgkin lymphoma (NHL) is still debated. CNS dissemination is a rare but fatal event. A CNS prophylaxis is common for Burkitt and B-cell lymphoblastic lymphoma; however, in other NHLs, prophylactic treatments are not systematically warranted. Current risk models showed low sensitivity in predicting CNS involvement, implying overtreatment in roughly 70% of high-risk patients. Risk models in the rituximab era were modulated for the detection of occult CNS disease at diagnosis using flow cytometry. The optimal regimen for CNS prophylaxis in aggressive lymphoma patients has not been established thus far and should be modulated at different levels of 'intensity' such as standard intrathecal chemotherapy, 'active' intrathecal chemotherapy with liposomal cytarabine or more aggressive systemic treatment with high doses of drugs having good CNS bioavailability reserved for patients who are truly at high risk of CNS dissemination.