Unlabeled and radiolabeled anti-CD20 monoclonal antibodies have had a significant impact in the care of patients with follicular lymphoma (FL) over the past decade. More recently, bendamustine has demonstrated activity in refractory FL, and has been explored as initial therapy and in novel combinations. Whereas outcomes for this patient population have significantly improved, there remains substantial unmet need for patients who require more effective and better-tolerated therapies. Novel anti-CD20 antibodies and other immunotherapies against different B-cell antigens are under active investigation. The proteosome inhibitor bortezomib and the immunomodulatory agent lenalidomide have demonstrated single-agent activity and are currently in randomized trials. Other novel compounds have demonstrated activity in broad-based clinical studies in B-cell malignancies. However, considerable challenges remain in efficiently demonstrating which patient subsets can benefit from these novel compounds and which combinations may have the greatest clinical benefit in further improving outcomes for patients with FL.