Follicular lymphoma is the most common indolent non-Hodgkin lymphoma. Although median overall survival rates exceed 12 years with rituximab, follicular lymphoma remains largely incurable. The growing understanding of the molecular drivers of lymphomagenesis and the tumor microenvironment have led to novel therapies. Prognostic markers have identified a subset of patients with chemoresistant and/or refractory disease-associated poor outcomes. We identify the patients with follicular lymphoma in need of novel therapies, describe the drivers of lymphomagenesis and importance of the tumor microenvironment, and summarize the novel agents under investigation in relapsed/refractory and upfront follicular lymphoma.