In this review, we summarize the indispensable role of EZH2 in lymphoid development, the variety of mechanisms of EZH2-related oncogenesis in lymphomas, lymphoid leukemias, and myeloma, how Epstein-Barr virus (EBV) impacts EZH2 signaling as a result of virus-host interplay and effective therapeutic strategies to harness EZH2 in different cancerous contexts. The gene discussed is EZH2; the disease is plasma cell myeloma.