Melphalan is an alkylating agent approved for the treatment of multiple myeloma and ovarian cancer. The combination of oral melphalan and prednisone was first introduced in the 1960s and remains the standard therapy for elderly multiple myeloma patients. High-dose melphalan followed by autologous stem cell support became the standard treatment for younger patients since the 1990s. The occurrence of drug resistance is the major limiting factor for the long-term success of this therapy, and relapse always occurs. In recent years, advances in the understanding of the pathogenesis of myeloma and the mechanism of drug resistance have led to the development of novel targeted therapies that are able to overcome resistance and show additive or synergistic effects with melphalan. Thalidomide, its immunomodulatory derivative lenalidomide and the proteasome inhibitor bortezomib, in combination with oral melphalan in the elderly and with intravenous melphalan in younger patients, are changing the traditional treatment paradigm of multiple myeloma.