Lymphomas are common malignancies that are prevalent worldwide. In recent years, some types of lymphoma have become curable, but relapsed and refractory lymphomas remain common and challenging. Impaired host immunity and therapeutic resistance are thought to play pivotal roles in the pathogenesis and progression of lymphomas. PD-L1 (programmed death ligand 1) is a newly discovered member of the B7 family of molecules, and its receptor is PD-1. It is known that the costimulatory signal of PD-1 and PD-L1 can help tumor escape from cellular immunity. However, little is known of the impact of PD-L1 on tumor cells, especially lymphomas. Our investigation shows for the first time that: (1) PD-L1 has a vital role in lymphoma oncogenesis; (2) the down-regulation of PD-L1 combined with chemotherapy can significantly suppress lymphoma growth, promote antitumor activity and prolong the survival rate; and (3) targeted therapy of PD-L1 may provide a new and promising approach to the treatment of lymphomas.