Primary CNS lymphoma can be subdivided into EBV⁻ and EBV-associated subtypes based on unique genetic alterations, gene expression signatures, and functional and microenvironmental differences. These biologic differences suggest that potential therapeutic strategies should be tailored within subtypes. ABC, activated B cell; amp, amplifications; BCR, B-cell receptor; BTK, Bruton tyrosine kinase; CAR T, chimeric antigen receptor T cell; del, deletions; IMiD, immunomodulatory imide drug; My-T-BCR, MYD88-TLR9-BCR supercomplex; mut, mutation; PI3K, phosphoinositide 3-kinase.