Maintenance therapy in multiple myeloma has been under investigation for more than 3 decades and has been without evidence of clear advantage in terms of progression-free survival (PFS) until the mid-2000s. Neither conventional chemotherapy, prednisone, nor interferon-based maintenance regimens offered any benefit after conventional or high-dose therapy. Thalidomide was the first drug, mainly given as maintenance after high dose therapy, to demonstrate clinical benefits in terms of PFS and, in some studies, of overall survival (OS). The role of other novel agents such as lenalidomide and bortezomib as maintenance therapy is emerging. Lenalidomide has been shown to reduce the risk of relapse with longer follow-up needed to see if this will translate into a survival benefit. At present, a number of key questions remain unanswered. What are the optimal dose and duration of those treatments? Is the risk of toxicity and second primary malignancies acceptable? Will the disease be more aggressive at time of relapse? Is the clinical benefit predicted by initial prognostic factors and response to previous therapy? Does maintenance therapy work by further eradication of minimal residual disease or by immunological control of the malignant clone? Ongoing randomized trials are evaluating lenalidomide and bortezomib, both in the transplant and nontransplant settings, to better define the role of these drugs as maintenance in multiple myeloma.