Thalidomide changed the treatment of patients with multiple myeloma, however, its effectiveness has been compromised due to its side effects. New strategies are needed to specifically target the challenges of multiple myeloma through innovative, more effective, and less toxic therapy. The new immunomodulatory (IMiDs) compounds are structural and functional analogs of thalidomide, which were designed to improve the immunomodulatory and anticancer properties and tolerability profiles. We review the development of second generation IMiDs, lenalidomide and pomalidomide, their immunomodulatory and tumoricidal effects, their mechanisms of action, as well as the influence of dexamethasone on their effect and pharmacological resistance. In conclusion, lenalidomide and pomalidomide demonstrate a powerful activity and they are highly effective and well-tolerated treatment options for patients with myeloma, used alone or in combination with dexamethasone.