Introduction: Lenalidomide is an IMiDs? oral immunomodulatory compound developed for the treatment of patients with multiple myeloma (MM) and myelodysplastic syndromes (MDS). Long-term continuous treatment with lenalidomide beyond first response may be important to optimize responses and delay relapse. Areas covered: This review summarizes the lenalidomide mechanism of action, pharmacodynamics, key clinical studies with a focus on safety and post-marketing surveillance data. The necessity for early adverse-event management, including dose modifications for neutropenia and thrombocytopenia, and venous thromboembolism prophylaxis, where applicable, in order to maintain patients on treatment and achieve optimal efficacy, is discussed. Secondary primary malignancies in MM and progression to acute myeloid leukemia in MDS patients in the context of lenalidomide treatment are also discussed. Finally, as lenalidomide is renally excreted, the requirement for dose adjustment according to creatinine clearance is discussed. Expert opinion: Lenalidomide is highly effective and generally well tolerated. Most adverse events occur early during the course of treatment and are manageable. Lenalidomide is not associated with peripheral neuropathy and has a lack of cumulative toxicity, making it an effective treatment option for long-term use in the management of MM and low/intermediate-1-risk MDS, specifically with chromosome 5q deletion with or without other cytogenetic abnormalities.