New treatment strategies in follicular lymphoma (FL) are driven by a deeper understanding of microenvironmental cues supporting lymphomagenesis, chemoresistance, and immuno-escape. These immune-mediated signaling pathways contribute to initial learnings and clinical successes with lenalidomide, the first, oral, non-chemotherapeutic immunomodulatory drug, combined with anti-CD20 antibodies. This combination of lenalidomide with rituximab showed similar efficacy to chemoimmunotherapy (CIT) in first-line patients requiring therapy, and is approved in relapsed/refractory FL. We review the biology supporting the rationale for adequate inhibitory receptor/ligand pathways targeting the tissue immune microenvironment of FL cells, and potential immunomodulating combinations to replace CIT in the near future.