In recent years considerable progress has been made in the treatment of patients with B-cell non-Hodgkin lymphoma (NHL). Although responses can be achieved with combination chemotherapy regimens, a substantial proportion of patients are still not cured. In recent years, the knowledge of the cellular and molecular biology of distinct types of B-cell NHL have led to the development of a new class of drugs that specifically targets unique disease-specific pathways. This review will focus on novel therapies that are being developed for the treatment of B-cell NHL including those targeting the B-cell receptor signaling pathway, the proteasome, epigenetic lesions, novel anti-apoptotic drugs, new monoclonal antibodies and immunomodulatory drugs.