SUMMARY CNS relapse is a devastating and frequently lethal complication in patients with lymphoma, and selecting patients to receive CNS-directed prophylaxis is a common and frequently challenging decision for the clinician. Histologic subtype, anatomic location, molecular and clinical risk factors may all be used to stratify patients for CNS risk. In this paper we focus on these issues and attempt to provide practical guidance for the clinician in selecting which patients with lymphoma may benefit from CNS prophylaxis.