Multiple myeloma (MM) is a disorder of clonal plasma cells that accumulate in the bone marrow and secrete a monoclonal protein detectable in the blood and/or urine. In the last decade, the outcome of patients with MM has markedly improved owing to the introduction of agents such proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide, lenalidomide) as induction, consolidation, and maintenance strategies. Nonetheless, drug resistance leading to relapse commonly occurs, and novel therapies are urgently needed. In this review, we will describe the most promising new approaches to treat MM, including those based on targeting protein homeostasis, enhancing anti-MM immunity, targeting MM with monoclonal antibodies and immunotoxins, modulating bone metabolism, targeting histone modifications, targeting genomic instability and cell cycle alterations, and the use of genomic profiling to provide personalized therapies. These advances will continue to transform MM into a chronic illness, and have curative potential.