Follicular lymphoma(FL) is the most common indolent non-Hodgkin lymphoma and constitutes 15% to 30% of lymphoma diagnoses. The natural history of the disease is characterized by recurrent relapses and progressively shorter remissions with a median survival of 10yrs. The impossibility of achieving a definite cure, have prompted investigations into the possible role of more active and less toxic strategies with innovative therapeutic agents. Recently Casulo et al. demonstrated that approximately 20% of patients with FL relapse within two years after achieving remission with R-CHOP and have a poor prognosis. It is conceivable that this particularly chemoresistant population would benefit from specifically targeting the biologic and genetic factors that likely contribute to their poor prognosis. Evolving strategies for difficult to treat FL patients have recently considered immunomodulatory agents, new monoclonal antibodies as well as drugs targeting selective intracellular pathways. The importance of targeting the microenvironment together with the malignant FL cell has been particularly underscored. We review the most promising approaches, such as combining anti-CD20 antibodies with immunomodulatory drugs (Lenalidomide), mAbs directed against other surface antigens such as CD22 and CD23 (Epratuzumab, Lumiliximab), immunomodulatory antibodies such as PD-1, or inhibitors of key steps in the B-cell receptor pathway signaling such as PI3K inhibitors (Idelalisib, Duvelisib). Another highly attractive approach is the application of the bi-specific T-cell engaging (BiTE) antibody blinatumomab which targets both CD19 and CD3 antigens. Moreover, we highlight the potential of these therapies, taking into account their toxicity. Of course, we must wait for Phase III trials results to confirm the benefit of these new treatment strategies toward a new era of chemotherapy-free treatment for follicular lymphoma.