Immune and nonimmune microenvironmental factors play a critical role in the progression, transformation, and resistance to therapy in follicular lymphoma (FL). A recent increase in our understanding of the role of microenvironment in FL biology has led to the development of novel therapeutic strategies targeting the nonimmune and immune microenvironment. These include immunomodulatory drugs, immune checkpoint inhibitors, immnunoconjugates, and small-molecule inhibitors with an impact on the microenvironment in addition to direct antitumor activity. These agents are now at different stages of clinical development, ranging from early clinical trials in relapsed disease to phase 3 studies in the upfront setting, including combinations with other agents such as monoclonal antibodies and chemotherapy. It is important to recognize that, although the current upfront therapy of FL is associated with favorable outcomes in the majority of patients, a significant proportion experience early disease progression and develop treatment resistance and transformation to aggressive lymphoma. Although the development of "chemo-free" combinations using drugs targeting the microenvironment offers a promising approach to minimize toxicity, the identification of patients at risk of relapse and the use of biomarkers allowing the personalization of therapy will likely play a major role in the development of maintenance strategies. Against this landscape of currently available therapy options, this chapter discusses the clinical status of therapies targeting the microenvironment in FL.