Over the last two decades, the outcomes for patients with multiple myeloma, a plasma cell malignancy, have dramatically improved. The development of the immunomodulatory drugs (IMiDs), which include thalidomide, lenalidomide, and pomalidomide, has contributed significantly to these improved outcomes. While thalidomide is now less commonly prescribed, lenalidomide is widely used in the treatment of newly diagnosed transplant-eligible and transplant-ineligible patients, in the maintenance setting post-transplant and in the relapsed/refractory setting, while pomalidomide is currently utilized in the relapsed/refractory setting. The IMiDs have been reported to have a multitude of activities, including anti-angiogenic, cytotoxic, and immunomodulatory. However, the more recent discoveries that the IMiDs bind to cereblon and thus regulate the ubiquitination of key transcription factors including IKZF1 and IKZF3 have provided greater insight into their mechanism of action. Here, the clinical efficacy of these agents in myeloma is reviewed and the structure-function relationship, the molecular mechanisms of action, and the association of IMiDs with second primary malignancies and thrombosis are discussed.