Frontline treatment for patients with indolent non-Hodgkin lymphoma often includes immunochemotherapy. Although the disease of most patients responds to initial treatment, relapse is common. Recent results from the phase 3 Augment trial showed that combining rituximab with the immunomodulatory drug lenalidomide (R2) significantly improved efficacy over rituximab monotherapy in patients with recurrent non-Hodgkin lymphoma. As a result of these data, R2 was approved in the US (Food and Drug Administration) and Japan (Pharmaceuticals and Medical Devices Agency) for previously treated adult patients with follicular and marginal zone lymphoma; and by the European Medicine Agency and the Swiss Agency for Therapeutic Products (Swissmedic) for previously treated adult patients with follicular lymphoma. R2 has also been studied as initial treatment, where results have been comparable, but not superior, to chemoimmunotherapy. The resulting expanded use of R2 reinforces the need for a detailed review of its safety profile and management, as presented here. Tolerability of R2 has been consistent among trials, with most adverse events (AEs) being predictable and manageable. Hematologic AEs, particularly grade 3/4 neutropenia; low-grade cutaneous reactions, such as rash; and gastrointestinal AEs represent the most common AEs associated with R2. The general R2 safety profile and optimal strategies for AE management are discussed.