Melphalan prednisone was the mainstay of myeloma treatment in the 1960s with 50% of overall response, yet this treatment was associated with a short duration of response and a poor median overall survival (only 3 years). Thalidomide, initially used as an antiemetic and sedative agent, was demonstrated to have substantial antitumor activity in multiple myeloma and other solid cancers. The first studies established a promising response among patients with relapsed or refractory disease. Melphalan–prednisone–thalidomide is currently the treatment of choice for a large proportion of elderly myeloma patients ineligible for autologous stem cell transplantation. Melphalan prednisone is appropriate only for a minority of patients with poor performance status and/or significant comorbidities. Thalidomide has opened a complete new field of novel agents termed the IMiDs^® class of immunomodulatory drugs; of which, lenalidomide (Revlimid^®, Celgene Corporation, NJ, USA) and pomalidomide (Actimid™, Celgene Corporation, NJ, USA) are the next and last in line developed agents, respectively. These options could lead to more personalized treatment approaches, based on patient comorbidities, as the novel agents have somewhat different toxicity profiles. Questions regarding the relative efficacy of melphalan-based regimens versus dexamethasone-based regimens with low-dose dexamethasone will require randomized Phase III trials. Additionally, the important issue of maintenance treatment needs to be further investigated. These new and emerging therapies offer multiple effective treatment options for multiple myeloma patients and greatly enhance the treatment strategies for clinicians.