In patients with follicular lymphoma, the prolonged clinical course consisting of multiple relapses is a fundamental challenge that requires clinicians to consider how to best balance treatment efficacy while minimizing toxicity and preserving quality of life. The treatment approaches and decisions regarding therapy are largely driven by the unique clinical features evident in each patient. The traditional treatment approaches for relapsed follicular lymphoma include chemoimmunotherapy regimens, targeted agents, radioimmunotherapy, and, occasionally, immunotherapy alone. The primary targeted agents used in the relapsed or refractory follicular lymphoma setting are the phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib, copanlisib, and duvelisib. PI3K inhibitors can have a significant toxicity profile. Radioimmunotherapy remains an underutilized option. The newest agent that has gained regulatory approval in the treatment of follicular lymphoma is tazemetostat, a methyltransferase inhibitor that inhibits and reduces the activity of EZH2. In June 2020, tazemetostat was approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory follicular lymphoma who have tumors that are positive for an EZH2 mutation (as detected by an FDA-approved test) and who have received at least 2 prior systemic therapies, or patients who have no satisfactory alternative treatment options. Data from a phase 2 study demonstrated that tazemetostat can produce clinically meaningful and durable responses, with a favorable safety profile, in heavily pretreated patients with or without an EZH2 mutation.