Abstract: As a second-generation immunomodulatory imide drug, lenalidomide enhances immunomodulatory effects while reducing neurotoxicity. It synergistically regulates adaptive and innate immune responses through both cereblon (CRBN)-dependent and independent mechanisms, and also exerts multiple biological effects including anti-angiogenesis and anti-fibrosis. Therefore, it has been gradually explored for the treatment of rare immune-mediated inflammatory diseases (IMIDs) in recent years. Existing studies suggest that lenalidomide has potential therapeutic efficacy in diseases such as immunoglobulin G4-related disease and Behçet'sdisease. However, relevant evidence is mainly derived from case reports, and its optimal dosage, applicable populations and long-term safety remain to be further verified. This review summarizes the mechanisms of action of lenalidomide and the research progress of its application in rare IMIDs, with the aim of providing references for future mechanistic exploration and clinical practice.