This substantial body of work describes the interaction between the viral protein EBNA2 and the host cell protein early B cell factor 1 (EBF1). The interaction of EBNA2 with the cellular transcription factor CBF1 is known to be required for transcriptional programming that occurs early upon infection of primary B cells. Using CBF1 deficient cell lines, the authors identify cellular genes regulated in a CBF1-independent manner and identify these promoter elements as being heavily enriched for EBF1 motifs. EBNA2 interacts with EBF1 via its N-terminal domain. The authors describe this interaction as an essential component in forming EBNA2-associated chromatin architecture. This work expands our knowledge of the complex transcriptional programming Epstein-Barr virus (EBV) utilizes in B cell transformation and identifies potential targets for developing therapeutics that combat latent EBV infection.