The purpose of this article is to review the current data on the risk of CNS relapse in patients with lymphoma and the efficacy of CNS directed prophylactic therapy. CNS relapse occurred in 30-50% of those with Burkitt lymphoma and acute lymphoblastic leukaemia/lymphoma prior to the introduction of intensified regimens that include CNS prophylaxis. Most patients with AIDS-related-lymphoma receive a short course of intrathecal prophylaxis but a re-evaluation of type and targeting of CNS prophylaxis is needed. Patients with diffuse large B-cell lymphoma (DLBCL) have a 5% overall risk of CNS relapse but a high risk sub-population can be identified on the basis of raised LDH and >1 extranodal site, testicular or primary breast involvement. CNS prophylaxis for selected patients with DLBCL may be justified by risk but its benefit is not yet proven. Intravenous methotrexate > or = 3 g/m(2) achieves therapeutic levels in CSF and parenchyma and in combination with intrathecal methotrexate would be a reasonable option for prophylaxis.