Richter syndrome (RS) is the transformation of chronic lymphocytic leukaemia (CLL) into aggressive lymphoma, in most cases diffuse large B-cell lymphoma (DLBCL). Here, the authors characterize the DNA methylation and transcriptomic profiles of RS samples, find a clonally-related CLL epigenetic imprint, and develop classifiers for “RS-type” de novo DLBCLs.